Resistance: Retribution occurs several weeks after the events of Resistance: Fall of Man for the PlayStation 3. James Grayson, a former British Marine, is the player. Grayson discovers his brother has been infected with the Chimera virus and destroys every conversion center he can find. The Maquis enlists Grayson to retake Europe from the Chimera. The game is a third-person shooter with a cover system allowing players to hide behind objects. Grayson can quickly emerge from hiding and attack the enemy while hiding from Chimera. When Grayson approaches the covers, they automatically lock, and aiming assistance is provided. Resistance 2 owners who play Resistance: Retribution on their PSP 2000 or 3000 can connect the AV output to a television to play the game with a DualShock 3 controller.
When both games are owned, they can be linked using a USB cable to access the Infected mode. It offers an alternate history that combines events from both games. Grayson is infected with a mutated version of the Chimeran virus after being recruited by Specter Lieutenant David LaSalle (from Resistance 2). In this game mode, Grayson wears a Specter uniform and has glowing Chimeran eyes. He can regain health, acquire new weapons, and breathe underwater. He can also access hidden passages and gather information, unlocking plasma grenades and a more detailed story. This game mode is terminated when the game is closed, and no progress can be saved. Multiplayer consists of Ad Hoc and Infrastructure battles with statistics tracking on MyResistance.net. Deathmatch, team deathmatch, containment, capture the flag, and assimilation are available in-game modes.