Three years after the Necromorph infestation aboard the USS Ishimura, Isaac Clarke awakens from a coma, confused, disoriented, and on a space station called The Sprawl. Just as his health begins to improve, The Sprawl is overrun with even more advanced forms of the alien-zombie hybrids.

Dead Space 2 takes place three years after the events of Dead Space, in 2511.

Following his nightmarish encounter on the USG Ishimura, former engineer Isaac Clarke arrives on the Sprawl, a civilian space station built on the remains of Saturn's moon, Titan, which was broken into pieces in a planet-cracking operation. Here a new Necromorph outbreak begins. Isaac witnesses the panic that overtakes the station from the start.