Dead Space 3 begins 200 years in the past for a short prologue that takes place on the icy planet Tau Volantis. Two soldiers in the colonial army are attempting to retrieve a codex at the request of a man called Dr. Serrano. The mission is compromised by the arrival of Necromorphs, and the commanding officer, in order to stop an outbreak, exterminates the surviving members of the team and destroys the Codex's data before committing suicide.
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In the present, we meet former protagonist Isaac Clarke dealing with his recent breakup with Ellie Langford. He's disturbed from his brooding by the arrival of EarthGov Sergeant John Carver and his colleague who are seeking Isaac's help. Ellie, as it turns out, has gone missing, so naturally Isaac agrees to offer his aid in finding her. However, while leaving Isaac's apartment, the three are attacked and pursued by Unitologist forces and one of the leaders, Jacob Danik, activates a Marker nearby. The group manages to escape, and they track Ellie's signal to Tau Volantis. Ellie and her team are successfully rescued from a stranded ship near the planet, but Isaac learns that Tau Volantis is the homeworld of the Markers, and he therefore insists that they land on the planet in order to end the Necromorph threat once and for all by turning off the Machine.
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After some run-ins with the Unitologists who were tipped off as to their location, Isaac, Carver, Ellie, and Santos, a member of Ellie's team, reach Tau Volantis' science facilities and manage to assemble Rosetta, an alien who created the Codex. Tau Volantis, as Isacc learns through a vision, is actually the home world of an alien race that, like humanity, also activated a Marker by accident. Tau Volantis' moon is a giant Necromorph, and the Machine keeps it inactive. Therefore, turning off the Machine, the goal Isaac was working towards, would wake the Necromorph moon. Horrified to discover that the Marker has been manipulating him, Isaac hurries to acquire the Codex before Danik can, but the latter turns up and heads for the Machine.
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Isaac chases him, and Danik, who has Ellie hostage, threatens to kill her unless Isaac hands over the Codex. Going behind his back, Carver grabs the Codex and tosses it to Danik who immediately turns off the Machine. The Necromorph moon begins to descend toward Tau Volantis, but Isaac and Carver are able to make it to the Codex and halt the Convergence Event. However, both men are trapped on the planet and presumed dead. Ellie, who escaped via shuttle, grieves Isaac's death while simultaneously taking comfort in the fact that the Marker is no longer a threat.
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In a scene after the credits, an audio log plays a message from Isaac as he calls out for Ellie to help him.