A squad of U.B.C.S mercenaries led by Klaus are sent to Raccoon City to secure an important scientist, Dr. Cameron. Using a handheld computer to track her location, the men are drawn to a warehouse in search of her, where a monster takes them by surprise and kills Roberto, one of Klaus' men. The creature is killed by an M203 round fired by Ed, but it's DNA spreads onto a cockroach, which listens into the squads conversation.
It then finds a rat and infects it, creating a cockroach-rat. The rat follows the remaining Umbrella team of four outside where they leave in their HUMVEE. It then uses tentacles to infect a wounded crow, thus giving it the ability to fly and follow the U.B.C.S They stop at a manhole where Dr. Cameron's signal is strong, then Norman, Roger, and Klaus decent into the sewers, with Ed guarding the entrance and vehicle. They stop where the signal is fixed and Norman breaches the wall with explosive charges. However, they find only Dr Cameron's equipment and a rabid dog, Klaus easily killing the animal with his sidearm. Downloading data from a nearby computer, Roger then reveals to Klaus that the monster in the warehouse was Cameron, and that they only needed to recover data on her research. Klaus, furious at how casually his men were used, throws him to the ground, Roger falling straight into the dog's corpse. Intending on returning to the vehicle, Klaus radios Ed, but the only reply is Ed's painted screams.
On the street, Ed futilely empties his assault rifle into the air as the infected crow tears at him. Norman climbs up the ladder, showered by the casing's from Ed's rifle. The manhole is obscured by smoke, when Norman falls off the ladder,in half. A monster climbs down the ladder, and Klaus fires several shots with no effect. The creature's face is exposed as that of Ed's and Klaus flees down the sewer.
He soon comes to an open hole in the wall, which he jumps through. Because the monster cannot fit through it, this buys him a short amount of time before it collapses the whole wall. He runs up a nearby manhole, where he sees the HUMVEE some distance away, along with a large number of zombies. Klaus executes a zombie point blank, then drops his sidearm for a second pistol, this one a Sig Sauer P225, carried in a leg holster. He sticks his pistol into a zombie's mouth and fires a single shot, the zombie seemingly unfazed. Tentacles burst from the ground and kill several zombies. Klaus' pistol is knocked away. he then tries to run back to the humvee until he is wounded in the calf by a tentacle. Writhing in pain, the creature closes in when Roger rams it with the Humvee. Klaus limps to the flatbed, and mans the M2 machine gun. After saying "I hope you understand, Ed..." he opens fire and tears the mutated Ed into pieces. The truck drives away and the city fades out.
Klaus wakes up a short time later in the front seat of the car. The time appears to be morning, judging by the sunlight. Klaus thanks Roger for saving his life, but Roger is silent. Klaus asks about the virus, and Roger explains how it moves among life forms, thus making it almost impossible to destroy. At this point Klaus sees a cockroach crawl into Roger's ear. A tentacle then bursts from his chest.
At this point Roger is revealed to have two faces, the second one being Dr. Cameron's. Cameron/Roger explains that she was watching them in the warehouse, in the body of the dog they later killed. She realized that Umbrella was after her research but she tells Klaus that he and the U.B.C.S members turned out to be perfect "guinea pigs" for the virus she had created. When they killed her, she infected a cockroach, and then infected Roger when he was copying files from her computer.
She then tells Klaus that she will be able to look normal and always get away from Umbrella. She delivers the final line of the film: "Umbrella will never get their hands on my research". She then uses two of her tentacles to pull Klaus' face apart, and the film ends.