It is quickly apparent that a Necromorph outbreak has infested the Sprawl, as Franco is attacked by an Infector and gruesomely converted into a Slasher before he can free Isaac's hands or even explain the situation. The game proper then begins, set three years after the ending of Dead Space (picking up immediately after the events of Dead Space: Ignition), as Isaac wakes up in a psychiatric ward, strapped into a straitjacket, and face to face with Franco Delille (the main character from Ignition). As Isaac provides an explanation, a vision of Nicole as a Necromorph appears, and screams the haunting line 'Make us whole' Isaac blacks out. Isaac explains how the Marker made him see things, such as his dead girlfriend. Foster is trying to make him recall what happened when he came in contact with the Marker. This takes place on Titan Station, a space station built into one of Saturn's moons, and nicknamed 'the Sprawl' by its inhabitants. The game then cuts to Isaac, at some point after the end of the first game, talking to a therapist, Edgars Foster. Nicole seems very happy about her job, but their conversation is cut short as the Ishimura flies out of communications range.

It's revealed that Isaac convinced Nicole to take the job aboard the USG Ishimura. This takes place at some point before the beginning of the first game. The game starts out with a transmission between Isaac Clarke and his girlfriend Nicole Brennan, whose suicide was a major plot twist in the original game.

The game was released on Xbox 360, Playstation 3, and PC on January 25th, 2011. Isaac Clarke now has lines of dialogue, however, the familiar formula of the original remains unchanged consisting of claustrophobic encounters in dark corridors as well as in open zero-G environments, tactical dismemberment with hard hitting engineering tools and lots of heart-pounding scares throughout.

In Dead Space 2, Isaac takes the fight to the Necromorphs, suggesting a much more aggressive style of gameplay than what was seen in the original Dead Space. The church of Unitology and the ominous Earth Government continue to play an important role in Isaac's fight against the Necromorphs. Following his encounter with the marker in the first game, Isaac is now plagued by disturbing visions. Set three years after the first game, the player once again takes control of Isaac Clarke as he continues his fight against the Necromorph threat.

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