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Chris Redfield, a former STARS member and now part of the Bioterrorism Security Assessment Alliance (BSAA), is directed to Kijuju, Africa and work with Sheva Alomar to apprehend Ricardo Irving before he can sell a bio-organic weapon (BOW) on the black market. They soon find nearly all the locals have been converted by parasites into Majini, and one of their teams has already been killed. They are rescued by the Delta team, including Sheva's mentor Josh Stone; in data provided by Josh, Chris sees a photograph of Jill Valentine, his old partner, presumed dead after a confrontation with Albert Wesker. Chris, Sheva, and Delta team close in on Irving, but he manages to escape with the help of a hooded figure, leaving behind documents that lead Chris and Sheva to oil fields in the marshlands where Irving's deal is to occur. They soon discover this was a diversion created by Irving to allow the deal to take place. Chris and Sheva attempt to regroup with Delta team, but at the rendezvous, find the team slaughtered by a BOW; Sheva cannot find Josh among the bodies. Chris refuses to report to headquarters, revealing his determination to learn if Jill is still alive.
Continuing in the marshlands, they find Josh injured but safe, and with his help track down Irving speeding away on a boat. Irving injects himself with a virus, mutating into a giant beast. Chris and Sheva defeat him, and with his dying words, direct the pair to a nearby cave to learn more. The cave, home of the Ndipaya tribe, is also the source of the plant that is used to create the Progenitor virus, the basis of the T- and G-viruses; Chris and Sheva find evidence that Tricell, the company supposedly funding the BSAA, had taken over a former Umbrella underground laboratory and continued Umbrella's research. Among the facility are thousands of capsules holding human test subjects; Chris discovers one that belongs to Jill, but when they search it, they find the capsule empty. As they leave, they discover Excella Gionne working with Wesker to send a number of missile with the Uroboros virus across the globe. Chris and Sheva pursue Excella, but are stopped by Wesker and the hooded figure, revealed to be Jill, enslaved due to a device on her chest. Excella and Wesker escape to a tanker while Chris and Sheva fight Jill, eventually subduing her and removing the device from her chest. After a brief reunion, Jill orders Chris to follow Wesker.
Chris and Sheva make their way aboard the tanker, and chase down Excella, who drops a case of syringes in her haste; Sheva holds on to a number of them. Wesker, via the ships intercom, reveals Excella has been infected with Uroboros, and she mutates into a giant monster which Chris and Sheva eventually defeat. The two chase down Wesker to a bomber aboard the ship loaded with the Uroboros missiles. Wesker overpowers them easily. Jill radios in that Wesker must take a drug regularly to maintain his power and that an overdose may kill him; Sheva realizes the syringes she found are doses of that drug. The two are able to subdue Wesker long enough to inject him with additional doses. Wesker attempts to escape on the bomber, followed by Chris and Sheva. They disable the bomber, which crashes into an active volcano. Wesker, still alive, injects himself with Uroboros, and starts to chase the pair through the volcano. Chris and Sheva eventually stun Wesker long enough and escape to a helicopter piloted by Jill and Josh. When Wesker attempts to drag the helicopter into the lava, Chris and Sheva kill him with rocket-propelled grenades, and the helicopter is freed. Chris ponders whether it is worth fighting to preserve humanity. He looks at Sheva and Jill and then decides that it is worth fighting for.