It picks up where the first game ended, with Gabe leaving Kazakhstan with his CBDC partners on his way to the U.S. The game is about getting the encryption codes and discs containing the virus data and finding a vaccine to cure Gabe's partner, Lian Xing, who was infected with the virus.
The game deals with the Omega Strain of the Syphon Filter virus, which was combined with mad cow disease to make it even deadlier. Players create their own agent from scratch, instead of assuming the role of Logan, but four bonus missions allow them to play as Gary Stoneman, Lian Xing, Lawrence Mujari and Gabe himself.
Gabe Logan is sent around the globe to uncover the latest threat to national security: another virus known as Dark Mirror. The PSP version features game sharing and online multiplayer. A PS2 port was released in 2007.
With the Syphon Filter threat finally neutralised, Gabe Logan is searching the globe for Lian Xing, who may be in danger, or a double agent. A corrupt government official, Robert Cordell, attempts to shut down the IPCA under presidential powers, and Logan is the target of an assassin.