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.[2]
Shortly after Carthage, the recruits are working under Stone in Belarus. The recruits are investigating Krivorozhstal Mill only to come under fire from Chechen military forces, killing off all the workers for transporting cattle contaminated with the Syphon Filter virus. The recruits are ordered to bring the workers to safety in an underground bomb shelter, while preventing the escape of a commanding officer named Zhidkov and saving the mill from destruction. Upon evacuation, the helicopter is shot down by Chechen forces in Mazyr, at Belaya Vezha. The recruits are separated by Stone and their pilot Alima Haddad. The recruits save Stone, but learn that Alima is missing and presumed dead. The team is extracted by IPCA pilot William Crusher.
Meanwhile Lian Xing undertakes a covert operation in Kyrgystan. She elliminates a North Korean agent Sok-Ju Yang, who was looking to buy the virus container, and a local businessman Askar Saydahmat, who acquired one of the two virus containers the CDP courier Yuschenko was carrying. From Saydahmat's files Lian discovers that CDP is going to sell the virus to YLA (Yemen Liberation Authority)[2]
The recruits are then deployed to Yemen, under the command of Mossad agent Ehud Ben Zohar. In order to get more information about the people behind the shipments of the Syphon Filter virus, Zohar has a lone recruit sabotage an arms bazaar while eliminating Chechen forces and gathering evidence. Zohar and the recruits take uniforms from the dead soldiers in order to infiltrate the Taherir Palace, facilitating the assassination and recovering documents about the arms shipments. Zohar succeeds in the assassination, but does not find the documents, unaware of Stone already stealing them. Crusher evacuates Zohar and the recruits, with Stone exchanging the information about the arms shipments for the viral container recovered by Zohar.[2]
The next mission places a recruit in Belarus, at Minsk University. The recruit is alone, supported by MI6 agent Maggie Powers and Crusher to plant surveillance equipment to track viral shipments. Meanwhile, Mujari is in Chechnya at Ivankov's hometown. Mujari takes photographic evidence of genocide, while stunning all SVR forces. With reluctance, Uri Gregorov was at the scene responsible for the massacre. Mujari takes a photo of Gregorov for the purpose of future blackmail, while picking up hidden clues in Ivankov's home.[2]
A lone recruit works with Mujari at a salvage rig recovering the wreckage of the S.S. Loreilei. The recruit plants four nuclear explosives at the lower level of the rig in order to prevent any future extractions of the Syphon Filter virus. The recruit attempts to cure Dr. Jandran, only for Jandran to die from the serum. Mujari issues an evacuation order on the PA system to prevent any civilian casualties. Crusher is killed in action.[2]
After the Lorelei operation, the recruits work under Lian Xing. The first mission is in Tokyo, at the Murakawa Tower. The recruits are ordered to eliminate Yakuza officers, infiltrate the building, search for surveillance tapes Lian planted, and recover computer data and virus samples while destroying the lab with C-4. After learning that an airliner Imani Gray boarded was shot down in Myanmar, Lian leads an operation to extract Imani's body while recovering belongings from a Korean agent Imani was tailing. The recruits slow down pursuing rebels via explosives, recover Imani's body as well as evidence that the airliner was attacked by terrorists, and eliminate a terrorist and the leader of the rebels.[2]
At this point, a frustrated and apathetic Logan decides to investigate Zurich against orders and takes a lone recruit with him to Switzerland to investigate Mihai Niculescu at the Niculescu Towers. While Logan investigates the main office, the recruit plants surveillance gear, and inserts data transmitters while searching the building for any incriminating evidence. The recruit finds the financial records for the ALA and a file incriminating the U.S. Secretary of Defense, Birchim. Upon the recruit's return to headquarters, Gabe travels to Budva, Montenegro at Niculescu's estate. While Mara Aramov and Niculescu are meeting, Niculescu tells Mara that he was going to have Ivankov nuke Russia. Aramov felt compelled to warn Russia, but passed out from a drugged drink. Gabe attempts to look for evidence incriminating Niculescu, saves Aramov, and learns that Niculescu is very meticulous when covering his tracks. Aramov tells Gabe where Ivankov's base is.[2]
The IPCA assaults Ivankov's base in Kiev, Ukraine, preventing the launch of missiles with chemical warheads, and rescuing Alima Haddad. Ivankov's fate is not revealed, but has been implied that he was killed in the explosion of the base.[2]
Thanks to tissue and virus samples recovered by the IPCA, a vaccine for the Omega Strain virus is successfully synthesized. The World Health Organization confirms that the Syphon Filter virus is no longer a threat as the vaccines are working. The President of the United States congratulates the IPCA. Birchim is arrested by Secret Service agents under the Homeland Security Act after Gabe shows the president the evidence of bribery. Stone carts off a wheelchair-using Alima. Dr. Weissenger is reported missing from a meeting with the WHO. No one knows where she went. Mihai Niculescu is killed by two anonymous gunmen as a result of the IPCA recruit planting a computer virus that wiped out the bank's records. Elsa Weissenger gives a written confession that she had the recruit kill Dr. Jandran, as well as signs of mental instability. Gabe sends a note to Mara Aramov. As Aramov reads the note, a rifle with a cracked scope appears, which reveals that Stone is sent to assassinate Aramov