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United States President Adam Benford plans to publicly reveal the government’s involvement in the 1998 Raccoon City incident during a seminar held at Ivy University in the American town of Tall Oaks. However, during the seminar, he suddenly mutates into a zombie after inhaling an infectious gas of the newly developed C-virus. The gas spreads rapidly, infecting nearly everyone on campus. Agent Leon Kennedy of the Division of Security Operations (DSO) shoots the reanimated President to save United States Secret Service (USSS) agent Helena Harper, who admits her involvement in the bioterror attack and promises to explain once they reach Tall Oaks Cathedral.

Resident Evil 6 promises to be the dramatic horror experience. Resident Evil favorites Leon S. Kennedy, Chris Redfield and Ada Wong are joined by new characters, including Jake Muller, to face a new horror, the highly virulent C-virus, as the narrative moves between North America, the war-torn Eastern European state of Edonia and the Chinese city of Lanshiang.