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Claire Redfield, Leon Scott Kennedy, and Ingrid Hannigan are voiced by their at-the-time video game actors; Alyson Court (the voice of Claire since her debut in Resident Evil 2), Paul Mercier and Salli Saffioti.
This movie marks the first and only canonical reunion of Resident Evil 2 protagonists Leon S. Kennedy and Claire Redfield since their original debut thus far.
Chris Redfield is referenced in the film when Leon and Claire discuss the career paths they took.
When Claire goes to look for survivors in the airport she was given an umbrella that had exactly the same colour pattern as Umbrella corporations logo to use as a weapon. Claire herself notes the irony.
Soundtrack clips from Resident Evil 2 game are used in the theatrical trailer.
When Frederic Downing shuts his office door, the sound of it closing is the same sound of players closing doors in the early Resident Evil games.
Curtis Miller's G-virus mutation is visibly similar to William Birkin's mutations from Resident Evil 2, most notably growing a huge eyeball-like tumor on his right shoulder.
At the end of the film, TRICELL is seen collecting the remains of Curtis. They would become one of the main antagonists in Resident Evil 5.
During Hardvardville's quarantine, there is a news reporter that has the same attire as Alyssa Ashcroft from the outbreak series.
This is the first film produced by Capcom. Hollywood's only contributions were the voice actors and live motion capture actors.
There is an iPhone game based on Degeneration, made using a simplified version of the Resident Evil 4 gameplay model.
Leon's jacket is modified slightly from his Bomber Jacket, to a leather HellCat Jacket.
In the Raccoon City flashback, while Leon talks with Claire, it shows Leon wielding his VP70 pistol and Claire wielding a M1100 Shotgun, which is odd, since Claire can't acquire a Shotgun in her storyline of Resident Evil 2.
The Army Rangers appear in this film in several scenes, but are referred to in the English localization as Marines. This caused some confusion among viewers due to them wearing Army Combat Uniforms and not the MARPAT uniforms typical of Marines at the time.