The game starts in Carthage, Michigan, when Imani Gray and four IPCA recruits are sent in to locate Lawrence Mujari, and eliminate the French Anarchiste Liberation Army (ALA) threat, while Gabriel Logan and Lian Xing investigate Uganda, with Gary Stoneman investigating Italy. The IPCA agents foil the ALA's plans. Mujari is recovered and under medical care.
Meanwhile, Stone discovers that Cosa Nostra want to retrieve the virus to use it as a tool in mafia wars. So Stone went on a mission to Pescara to assassinate the mafia head, Dimitri Alexoupolos. Dimitri's assassination prevented a Mafia family from gaining access to Syphon Filter.
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