Two years after Naraku's defeat, Sesshomaru has begun to travel feudal Japan in search of a worthy opponent with his two companions, Jaken and the two-headed dragon. Along the way, Sesshomaru encounters a mysterious human woman who frequently travels to the Netherworld in search of a mighty weapon. Could she be the opponent he's looking for?

The world has been plagued by the T-virus down to the last bits of humanity residing in the White House. In a research facility located underground, Carlos Oliveira is found by a mysterious woman who has the Red Queen, Chris and Claire Redfield, and Chad Kaplan as her aids in defeating Wesker and dispatching a bomb that will wipe out the T-virus. Will they survive and defeat him?