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Upon reaching the Government Sector, Isaac sends Ellie away alone on a gunship which she is expecting him to get on with her. Eventually he comes to accept that he cannot run away anymore and that his destiny is to sacrifice his life to stop the Marker, causing the Nicole visions to become friendly and peaceful. As Isaac fights his way to the Marker, his visions of Nicole become more vivid as she tries to deter him from his task. She survives and later Isaac is forced to kill Stross in self-defense. Later, Stross' dementia worsens leading to him attacking Ellie. As they progress through the Sprawl, the station's administrator, Hans Tiedemann, throws several obstacles in their way to stop them from getting to the Marker. As Isaac makes his way there, he comes across another survivor, Ellie Langford, a CEC officer who eventually joins their mission, deciding that she needs their help to survive.

He tells Isaac that the Marker is located in the Government Sector under lockdown. Stross contacts Isaac again and he reluctantly decides to trust Stross, as his only mission now is to destroy the Marker. As they are about to leave, a Gunship guns down Daina and her associates, allowing Isaac to escape. Upon his arrival, two guards seize Isaac as Daina reveals that she is a Unitologist sent to “recover” Isaac, claiming that he is responsible for building the Marker that is causing the current infestation and that they need him to build more. Ignoring Stross, Isaac fights his way across the city, making his way to Daina. He is also contacted by another patient, Nolan Stross, claiming he and Isaac can destroy the Marker. He is later contacted by a woman named Daina Le Guin, who guides him to her location. However, before he can remove the straitjacket, Franco is killed and transformed into a Necromorph, leaving Isaac to escape on his own. Isaac Clarke has no memory of the last three years, having just been released by Franco, the protagonist of Dead Space: Ignition.

The game begins in a hospital on the Sprawl, a densely populated metropolis built on a shard of the moon Titan, Saturn's largest moon.

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