Following the destruction of the first Syphon Filter virus, the Agency has received a new cover as the International Presidential Consulting Agency, dedicated to battling terrorist enemies. Gabe Logan, as Commander-in-Chief, has hand-picked a team of leaders and agents for his new organization, including Lian, Teresa, Mujari, Elsa Weissinger, and more.
The past returns when Syphon Filter reemerges as the deadlier Omega Strain. A Chechen officer named Mikhas Ivankov is selling it on the black market, and outbreaks are occuring around the world. The man behind the conspiracy, Mihai Niculescu, sends Mara Aramov to find and eliminate him. Meanwhile, Gabe and the Agency split up and investigate locations of certain outbreaks.
An Agency team headed by Imani Gray visits Carthage, Michigan in search of Mujari, who disappeared while investigating Dr. Richard Broussard. Broussard had made a deal to give the virus to terrorists from the Anarchiste Liberation Army, but he backed down. The ALA acquired it anyway, and attacked the city. Imani and her team rescue Mujari to find the Omega Strain has infected him. The agents defeat the two ALA leaders, Soren Masson and Jean Fournier, and prepare for their next assignment. In Uganda, Gabe shows his obsession for stopping the Syphon Filter conspiracy.
IPCA commander Gary Stoneman tells the Agency operatives about his history as an assassin for the CIA, and how he recently killed mafia leader Dmitri Alexopoulous to keep him from obtaining the Omega Strain in Italy. The team follows Stone to Belarus and tracks a shipment of infected cattle which leads to the residence of Ivankov. They discover that his courier Yuschenko is selling the Omega Strain, and Agency pilot Alima Haddad ends up taken by the Chechens. Stone assumes the worst.
Lian later tells the Agency team how she identified that North Koreans were attempting to purchase the virus. She infiltrated the domain of warlord Askar Saydahmat and found his people were about to give the Omega Strain to Sok-ju Yang. Lian eliminated both of the involved parties.
Gabe enlists help from Ehud Ben Zohar of the Israeli Mossad upon determining that Yuschenko plans to sell the virus to Fatha Al-Hassan, a Yemeni leader. Zohar only cares about stopping the man's terrorist connections, so he steals the viral canister after the Agency retreives it from Yuschenko, and uses it to force Gabe's people into helping his mission.
Zohar and the team enter Al-Hassan's palace disguised as the dead Chechens. After Zohar eliminates Al-Hassan, he searches for evidence of weapons contracts while the Agency defends him. Stone arrives to save them, and reveals that Gabe sent him in case Zohar tried any tricks. They exchange the contracts for the virus.
Next, the team investigates a lead recovered from the Belarus operation that shows Dr. Nikolai Jandran is conducting virus tests. Maggie Powers assists them in breaking into Jandran's labs and recording evidence. The team must escape before enemy forces destroy the university where Jandran works.
Mujari, having recovered from the virus, explains his own investigation into the Chechens and why Ivankov wants independence from Russia. He sees that Uri Gregorov and other Russians are imprisoning the rebels, and finds hints of atrocities. Mujari knows both sides have reasons for what they do, and the situation is not black and white.
Afterwards, Mujari takes control of the Agency team as they check the wreckage of the S.S. Lorelei. The university turned up salvaged boxes, indicating an undersea operation. Mujari does not allow his team to kill innocent guards, and he evacuates the salvage rig before the Agency's planted nukes destroy the viral containers for good. However, Jandran dies from a serum prepared by Elsa.
While Gabe faces pressure from the president and Alex Birchim of the White House Internal Affairs, he sends Lian and the team to track North Korean agent Yong-jun Kim, a man connected to Murakawa Industries in Japan. The investigation reveals that Murakawa, a part of the Yakuza, was helping to develop the Omega Strain. Aramov arrived before Lian and forced Murakawa to commit suicide for trusing Kim. Kim pretended to work with Murakawa so he could get the virus.
Unfortunately, the team hears tragic news after destroying the Japanese labs. Imani had been tracking Kim on an airplane that crashed in Myanmar. Out of guilt, Lian takes the team to recover her body and the viral sample Kim was carrying. They find a letter indicating that Aramov had paid the Myanmar army to shoot down the plane.
Gabe becomes frustrated with his investigation into the secret corporation Meta Global Funds, which he believes controls the Syphon Filter conspiracy. The purchase of Murakawa Industries by Meta Global was possible through Niculescu Funds, headed by international banker Mihai Niculescu. He is powerful and influential, but secretive as well, so Gabe suspects he is behind Syphon Filter. Against Birchim's commands, Gabe brings the Agency team to the Niculescu Funds headquarters in Zurich. They break in and find evidence linking Birchim to bribes, but nothing implicating Niculescu.
Gabe will later describe the rest of his investigation to the Agency team, and how he looked into Niculescu's Montenegro estate in a final effort to expose him. Although he did not find physical evidence, he learned that Mara was working for him, but Mihai betrayed her. Mara did not want Ivankov to destroy Moscow, for he traded the Omega Strain to the North Koreans for a nuclear weapon.
Having learned of Ivankov's location from Mara, the Agency mobilizes to his base and works to prevent the missle's launch. Stone recovers Alima, injured but alive, and the team works with Gabe to disable the missile. Ivankov seemingly perishes afterward.
Weissinger and Mujari cure the Omega Strain and destroy the final traces of Syphon Filter. Meanwhile, criminals eliminate Niculescu after an Agency computer virus erases the money of his illegal clients. Government officials arrest Birchim after Gabe shows the President files linking Birchim to bribes. The conspiracy is over, and Gabe can focus on other threats. Just when all seems normal, Elsa Weissinger resigns from the Agency, confessing that she had met Mihai Niculescu before. She intended to kill Jandran as well, believing that her destiny is to change the world. Elsa exits from the Agency base, and Gabe wonders what will happen next.
- IPCA European Command: Training Centre
- Carthage, Michigan: Quarantine Zone
- Carthage, Michigan: Warehouse District
- Carthage, Michigan: Carthage Mall
- Pescara, Italy: St Cetteo's Square
- Mazyr, Belarus: Krivorozhstal Mill
- Mazyr, Belarus: Belaya Vezha
- Tash, Kumyr, Kyrgysztan: Saydahmat's Village
- Sana's, Yemen: Arms Bazaar
- Sana's, Yemen: Taherir Palace
- Minsk, Belarus: International University
- Samaschki, Chechnya: Ivankov's Home
- North Atlantic: Lorelei Salvage Rig
- Tokyo, Japan: Murukawa Tower
- Taguang, Myanmar, Irawaddy Basin
- Zurich, Switzerland: Niculescu Funds Tower
- Budva, Montenegro: Niculescu's Villa Estate
- Kiev, Ukraine: Chechen Terrorist Base