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Dr. James Marcus, a founder of the Umbrella Corporation, has a daughter named Alicia who suffers from progeria, a fatal disease that causes premature aging. He has already lost his wife to the disease and scrambles to find a potential cure. Against all odds, Marcus finally finds the solution with the T-virus. It is a miraculous find that could cure thousands of life-threatening diseases. It saves Alicia’s life, but it has unforeseen side effects. Within a cable car riding along through the mountains, a boy suddenly collapses and chokes to death. Suddenly, he wakes up with milky white eyes and suddenly attacks a nearby passenger. Soon, all the occupants inside are bitten and become the first of the undead. It is discovered by Umbrella after that the boy had a life-threatening condition cured by T-virus-derived medication, but once he died, the virus reanimated his dead cells and brought him back to life. Umbrella quickly covers up the incident and it never becomes public.
Back at Marcus’ house, Marcus and Isaacs argue furiously about what should be done with their invention. Marcus claims that it is too dangerous and wants it to be contained and destroyed. Isaacs, on the other hand, wants to profit from it and use it for military purposes. Marcus refuses to support Isaacs’ plan and states that they created the company to help people, not hurt them. Isaacs scoffs, saying that he has changed and nods at Wesker, who is hiding in the corner. Wesker quickly rushes up behind Marcus, puts a plastic bag over his head, and watches as he suffocates to death. Just then, Alicia walks down the stairs to see what’s going on, but Isaacs shoos her away, saying that everything is ok.
Isaacs is now essentially in complete control of Umbrella, with only Marcus’s young daughter Alicia in the way. She is too young to realize her responsibility of owning a large company, so he makes all of the decisions. Within a few years, Umbrella grows into one of the most powerful commercial entities in the world. To help control the company, Isaacs develops an AI as a tribute to Alicia, which he calls the Red Queen. Ten years later, the Raccoon City Outbreak occurs and while the city is destroyed, it is not the end of the terror as the Global T-Virus pandemic sweeps across the world in just weeks, decimating humanity.
Ten years after the outbreak, Alice wakes up in a pile of rubble, having been led to Washington, D.C. by Wesker. Everyone is gone, and she groggily stands up, walking to a nearby river to get a drink of water. Suddenly, she attacked by a monster that rises up out of the water. Having no weapons, she kicks it off and sighs and relief as she notices that its leg has been chained, making it immobile. She runs away and tries to find weapons. She picks up a few basic guns and is about to walk out when a Kipepeo rises from the rubble and attacks her. Alice finds a humvee and dives into it for safety. She gets it to start up and after a long pursuit by the monster, she finally kills it by blowing up the gasoline within the vehicle. Shaken and stirred, she heads in an abandoned building to recover. She hears a noise and investigates the source. It turns out the be the Red Queen, who says that she needs to talk to her.
The Red Queen claims that she has switched sides and is working against Umbrella now, and is willing to help Alice. She says that Alice has 48 hours to head to the Hive and resets her watch. Alice is wary and demands why she should trust her. The Red Queen says that inside the Hive is a cure for the T-Virus, a potent airborne anti-virus that when released, will kill any T-Virus infected creatures on contact, essentially stopping the pandemic. She also says that this is a chance for Alice to get revenge on Wesker and Isaacs. Alice is convinced and tells the Red Queen she’ll be there. She takes a nearby car and heads off towards Raccoon City.
While driving past some of the Undead in her car, her tires get shredded by some barricades and her car crashes, rendering it useless. Alice groans as she looks at her watch and starts off on foot. While walking towards a nearby overpass, she spots a motorcycle underneath it. She runs up to it, but is wary when she sees the Umbrella logo on it. She carefully approaches the motorcycle, but is suddenly ambushed by a Umbrella soldier hiding underneath the rubble. Alice steps back to dodge, but finds herself surrounded by four other soldiers. She sets off a trap, in which a rope comes down, pulls her upside down towards the ceiling and renders her immobile. The soldiers start beating her nightsticks, and Alice just laughs, asking if “that’s all they got”. One of the soldiers rush her, and she quickly grabs him, using his gun to kill the other soldiers and free herself from the trap. With the coast clear, she hops on the motorcycle. She tries to turn it on but gets electrocuted by it, finding that it only works for authorized Umbrella personnel. She falls unconscious from the shock.
She wakes up in a small cell, accompanied by other prisoners, then questions where she is. Isaacs enters the cell surprising Alice that he is still alive. He reveals that the Isaacs she killed was a clone then begins to question her. Isaacs begins demanding information, refusing to answer him, he then casts her out. When they do, Alice finds that her cell was within a giant Umbrella tank, which is being followed by thousands of the Undead. Isaacs then contacts Wesker questioning him about Alice's survival, claiming she has knowledge of the anti-virus. Her hands are attached to a rope tied to the tank, but she must continue running to avoid being grabbed by the Undead. There are two soldiers monitoring her from atop the tank and she tricks them by ducking underneath the back of the tank. When one of them leans over, Alice uses him to pull herself up, and in the process, pulls him down and throws him to the Undead. Another solider investigates the noise, and is knocked off the tank.
Isaacs senses trouble from watching the cameras and climbs to the top of the tank to take care of Alice himself. They have a brutal knife fight on top of the tank, with both of them almost falling off into the crowd of undead several times. While fighting, Alice forces Isaacs to free her, then presses a switch on top of the tank, opening a compartment containing a motorcycle. Isaacs taunts that she will be unable to use it, so she simply cuts off his hand, uses it to turn on the motorcycle, and speeds away from the tank. Crying out in agony, Isaacs instructs the driver, Lee, to use the turrets and lock-on missiles to try and take her out. He misses and she is successfully able to get away.
Several hours later, she finally arrives at the outskirts of Raccoon City. She sees that the bridge leading to the city has been completely destroyed, so she has to go the long way around, through the rubble. As she approaches a spiral-tower like building, a light flashes from above and a heavy object comes crashing down, shattering her motorcycle and rendering Alice unconscious. Waking up, she finds herself tied up and surrounded by several armed people, all of them yelling questions at her. She is about to get shot until Claire enters the room and recognizes her. Claire orders her to be untied and introduces the people to Alice. Their names are Doc, Christian, Abigail, Michael, and Cobalt. They explain that they have been sheltering in the skyscraper for a while, essentially turning it into a fortress. Alice collapses from coughing and Claire takes to the makeshift hospital to receive treatment.
While there, Claire explains how she had escaped from Umbrella and got involved with the survivors in the building. Alice says that Isaacs is coming their way and explains her mission to get the anit-virus from the Hive. Claire is in shock and exclaims that Alice would die if it were released. Alice simply says “whatever it takes” and Claire grudgingly agrees to help her, but only if she stays to help the survivors defeat Isaacs. Alice agrees and they get to work on their defenses. She finds that there isn’t much weaponry available, but there is a lot of gasoline. Using this knowledge, they construct catapults to take out the tanks and the undead. Their work completed several hours later, Alice spots Isaacs and his army of Undead approaching the building. Alice tells the residents to brace themselves and they ready the catapults.
There are two tanks approaching the building and they catapult a flaming projectile at one of them, destroying it instantly. Isaacs is within the other tank and instructs his soldiers to bring out the “bait”. A survivor is released from the tank, with thousands of Undead following her and Alice instructs the residents to open the building for her. Unfortunately, she is shot by a soldier and some of the Undead get into the building before they are able to close the gates. Isaacs sees his chance and instructs Lee to fire the turrets on the roof, where Alice and the survivors are staying. Meanwhile, Claire, Michael, Cobalt, and Christian were struggling to hold back the Undead on the bottom floor. Cobalt gets bitten by one while holding the barricade and dies. In horror, Claire yells to Alice that the barricade won’t last any longer and Alice yells at them to come upstairs, having a plan of her own. Alice and Abigail pour gasoline onto the bottom floor from the roof, light it up with some torches, and incinerate all of the Undead on the bottom floor. With all of her companions safe for now, Alice ziplines to the ground and rushes to get to the tank. From within the tank, Lee spots her on the camera and opens fire. Alice hides behind some rubble and is able to get on top of the tank. She pours gasoline into it, lights a match, and watches as it explodes, seemingly killing everyone within it. However, Lee is somehow able to escape and knocks her to the ground.
The two have a quick fight, with Lee winning easily. Kneeling on the ground, Alice lets one of the Undead attack Lee from behind and he is able to dispatch it easily. This leaves him open to counterattack, and Alice seizes the moment, shooting him and seriously wounding him. Alice leaves him to die on the ground and meets up with the other survivors. Two prisoners from inside of the tank, The Thin Man and Scars, beg to come along with them. Alice lets them join the group and prompts them to get some gear. She urges everyone to follow her to the Hive and the group make their way to Raccoon City on foot. Unbeknownst to them, Isaacs is still alive and watching them from behind a pile of rubble. He seizes another tank that is driving by, kills all of the occupants, and follows Alice and her companions to the Hive.
Alice and her group get to the edge of the crater that was once Raccoon City, they climb down and move through the barren wasteland. From within the Hive, the Red Queen instructs Wesker that they are extremely close to reaching the Hive and he orders the release of monstrous dogs to keep them at bay. The dogs appear out of nowhere and attack Alice and her companions. They shoot at them and sprint as fast as they can until they reach a cliffside. Without hesitating, they jump off of the cliff and land in the water. They swim to shore and continue onto to the Hive. Moments later, they finally find the entrance to it, but the dogs are suddenly in pursuit again. Alice yells at her companions to run and they finally get inside of the entrance.
Oddly, the dogs stop chasing them once they get through the entrance, because something scares them away. Hesitating to enter, the group is unsure of what to do. Watching the group on a camera, Wesker orders the entrance to be sealed, and the door starts closing. The group rushes through, despite the ominous nature of the place. While going through, Alice is suddenly attacked by one of the Undead. She is able to barely hold him off and escape before the door closes, crushing the Undead to death. Struggling to catch their breath, they continue until they reach a podium, where the Red Queen greets them. She shows them a video of an Umbrella meeting where Isaacs is planning to stage his own apocalypse using the T-Virus, killing everyone on the planet except himself and other high-ranking Umbrella executives. The Red Queen explains that she has been programmed not to hurt others, so she is on their side due to the murderous nature of Isaac’s plan. At the same time, she is unable to hurt any Umbrella employees, which is why she needs Alice’s help. She gives Alice an earpiece so they can communicate wirelessly. Before they leave, the Red Queen informs her that there is a traitor within the group and Alice shrugs it off, vying to proceed into the Hive.
As they walk through the main hallway, they find that the power has been cut off and that there is a giant fan impeding their progress. The group groans and complains, but Alice simply walks through the motionless blades and instructs the others to do the same. Wesker orders the fan to be turned on, and the group barely make it through. He is not done yet however, as he sets the fan to suck in air, which sends the group flying back. Luckily, they are able to hold onto some poles on the ground. Unfortunately, Abigail has lost her grip and only has Alice to hold on to. After a long struggle, the fan sucks Abigail in and shreds her to bits, finally turning off. The devastated group watches in shock and glumly continue on. Wesker is satisfied that he had killed off yet another member of Alice’s group and plans his next trap.
Alice and the group have found themselves within a vent and are crawling through it when a light suddenly comes on. Stopping in fear, they await what lies ahead. When nothing happens, they reluctantly move forward. Suddenly, a section of the floor opens up and the Thin Man falls into it. It turns out to be a shaft, too deep to climb out of. There is a clear opening underneath him and it opens up, dropping him. He hangs on to the opening, but the door shuts, breaking his fingers and dropping him to his death in a cavern hundreds of feet below. Now, only Alice, Claire, Doc, and Michael are left surviving. Trap doors open up for them as well, hurtling Alice down into a dark laboratory and Claire into a glass box.
Alice groans in pain and gets up, quietly walking around. She hears a noise, and is relieved to find that it’s Michael. The two carefully walk around until Michael is attacked by a Licker-like monster. He is killed instantly and Alice shoots at it and runs away. She leads the monster to a chain, wraps him up in it and runs, letting the chain go taut. The monster is choked by the chain, but still manages to attack Alice. She shoots it into submission, but not before taking another set of injuries. Tired and worn out, she proceeds to find an exit, and meets up with Doc. Meanwhile, in the glass box, Clare uses gunpowder to blast a hole and escapes.
Alice and Doc enter the laser corridor on their way to the interior of the Hive, giving Alice bad memories about what happened the last time she was inside of the room. She tells Doc to hurry and they get to the other side, finding Kaplan’s equipment from 10 years before still lying on the ground. Alice takes two guns out, and gives one to Doc. She inputs commands into the computer and it turns out to be an elevator, which they take to the bottom floor. During their ride, they spot thousands of bodies in cryogenic storage, which Alice angrily recognizes as high-ranking officials of Umbrella, waiting out the incident. She takes a bag of explosives that she found within Kaplan’s bag and asks for Doc’s help in rigging the Hive to explode.
In the control room, the Red Queen informs Wesker that Alice will be there soon. He instructs her to take Isaacs out of cold storage to prepare for her arrival. Back to Alice, her and Doc step off the elevator and find themselves in a cavern, the same one that the Thin Man has fallen into. They cautiously walk past his mutilated body and walk across an illuminated walkway across the water. A voice calls out to them from the other side and Alice recognizes it as Isaacs’. He leads them to a fancy bunker and demands that they drop their weapons. Alice drops hers, but she notices that Doc hasn’t done the same. Revealing himself as the traitor, he points his gun at her and forces her to drop her gun and detonator. Claire walks in moments later, with Wesker holding her hostage. Isaacs shows them the antivirus and Alice looks around for any potential ways to hurt Isaacs. She looks at the table and finds a decanter, fountain pen, and a bust, but Isaacs laughs, telling her not to bother, because she wouldn’t be able to get to any of them in time.
Isaacs explains that he is the original version of himself, and that the Isaacs that Alice had fought on the tank was a clone. Furthermore, Alice herself is a clone. Isaacs points to a cryostasis tube inside of the room and an old woman walks out onto a wheelchair. He introduces her as Alicia Marcus, the co-owner of Umbrella and the daughter of James Marcus. She is who Alice herself is based on. Isaacs explains that is not much older than Alice is, but that she suffers from progeria, which accelerated the aging process. Isaacs says that he has been waiting for years for her death, which is the moment when he would be able to assume complete control of Umbrella. Alicia exclaims that she still owns 50 percent of the company and scoffs that Wesker is just an employee. Wesker coldly claims that he is loyal to Isaacs and Alicia fires him, allowing the Red Queen to harm him. The Red Queen quickly lowers a blast door next to Wesker that crushes his leg, immobilizing him and causing him to quickly losing blood.
Claire is freed in the process, and Isaacs runs away, heading back to the main computer to transfer complete control of the company to himself. Claire shoots Doc to death with a headshot for his betrayal and Alice leaves the detonator in Wesker’s hand, knowing that once he goes unconscious, it will go off. Alicia gives the two the anti-virus and tells them that they must hurry and get to the surface to use it before Isaacs gets there. They head off in pursuit of Isaacs. They corner him in the elevator and find that he has inhuman strength and speed, allowing him to dodge all of their bullets. Claire becomes incapacitated, and she yells at Alice to go ahead.
Isaacs traps Alice in the laser corridor and turns the power on. She successfully dodges all of them and unamused, Isaacs rushes in to attack her himself. He lands several devastating blows on Alice and even cuts off her fingers using the laser grid. When Alice is on the edge of defeat, she laughs and reveals that she had pulled the pin to the grenade inside of his pocket. The grenade explodes, causing Isaacs to fly back and kills him.
From there, Alice sprints to the exit of the Hive and makes it out just as the detonator falls out of Wesker’s hands and blows up the facility. She is about to release the anti-virus when a still-alive Isaacs appears and catches it before it hits the ground and breaks. He holds her at gunpoint and is about to shoot her when suddenly, his clone rushes up to the two, having led an entire army of Undead to the area. The real Isaacs tells the clone that he is fake and in retaliation, the clone viciously stabs Isaacs to death, allowing Alice to get the anti-virus. The clone is bitten by an undead and Alice finally has the chance to release the anti-virus. It shatters and all infected individuals within the vicinity die instantly, including herself.
Several hours later, Alice wakes up, finding that Claire had also made it out. She wonders how she is still alive because she had been infected with the T-Virus. The Red Queen appears and explains that the anti-virus had only eradicated Alice’s infected cells, but left her healthy cells untouched allowing her to survive. It is also revealed that before she died, Alicia uploaded memories of her childhood for Alice, allowing her to have a semblance of her childhood back. Alice weeps at this and vows to continue her mission. Finally, Alice is seen riding her motorcycle through the desert. She explains that it will take several years for the anti-virus to completely eradicate the T-virus, and until then, her mission is not over.