Set in the distant future, Dead Space revolves around Isaac Clarke, a space engineer who works for the Concordance Extraction Corporation (C.E.C.), a company that operates giant mining ships throughout the galaxy. When the C.E.C. receives a distress call from the USG Ishimura (a “Planet Cracker”-class ship that destroys planets in order to extract valuable ore), Isaac and four other C.E.C. employees set out on the USG Kellion to rendezvous with the Ishimura in orbit above Aegis 7. Their assumption is that a mechanical failure is the only problem. At the beginning of the game, Isaac is seen watching a video sent to him by his ex-girlfriend, Nicole Brennan, who is currently on board the Ishimura.
Shortly after crash landing on the Ishimura flight deck, the crew of USG Kellion is attacked by hostile creatures called Necromorphs. These creatures reproduce by reanimating deceased human bodies, violently mutating and assimilating them to become one of their own (A process referred to by a scientific backstory log as "Recombination"). Isaac escapes down an elevator and kills a Necromorph by trapping it in the elevator doors, but is separated from the rest of the team. At this point, Isaac, Kendra Daniels, and Zach Hammond are the only surviving members of the USG Kellion.
Throughout the rest of the game, Isaac is tasked with repairing different areas of the Ishimura while constantly under attack by Necromorphs. Eventually, Isaac, Kendra, and Hammond send out an S.O.S beacon attached to an asteroid. This attracts a military vessel, the USM Valor. Unfortunately, the Valor retrieves an escape pod that Hammond had used to trap a living Necromorph, infecting the crew of the Valor, resulting in a ship-to-ship collision with the Ishimura. Also, Isaac is confronted by one of the only survivors left on the Ishimura, a now-demented Dr. Charles Mercer. Mercer believes that the Recombination of the Necromorphs is "God's work", and thus should not be resisted. Even more disturbing, Mercer experimented with several captured Necromorphs in order to make an unstoppable Necromorph that could regenerate any injured body parts. In order to attempt an escape with Kendra and the ship's science officer, Dr. Kyne, Isaac must repair a damaged shuttle. However, Kyne wishes to use the shuttle in order to return the Marker, a religious artifact that is somehow linked to the infestation, to Aegis 7. Hammond is killed by a large and powerful Necromorph while Isaac is returning with an intact Singularity Core that will power the shuttle. Doctor Mercer also makes one last appearance trying to kill Isaac with his Necromorph experiment, and then willingly becomes a Necromorph himself.
Just before the ship lifts off, Isaac is betrayed by Kendra, who kills Dr. Kyne and reveals that she is a government agent attempting to salvage the Marker, which is actually a copy of a real Marker found on Earth. While the original Marker was of alien origin, the copy was man-made and had been placed on the planet. It was later found by the colony and eventually moved to the Ishimura, unleashing the Necromorph infection.
Isaac, left to die on the Ishimura, is saved by his Nicole, who recalls Kendra's ship and sets it to fly her and Isaac to Aegis 7. After a long transport to the crater, the Marker finally brings the Necromorphs under control. The blast from the Marker as it reactivates disables the machinery holding a large piece of Aegis 7 in orbit, where it was being held in preparation for mining. Kendra removes the Marker to bring it back to Earth. She tells Isaac that he is as demented as Dr. Kyne, and urges him to watch the final half of Nicole's message: her suicide, where she uses a hypodermic needle to inject an unknown substance into her arm. The Marker used an image of Nicole to get Isaac to return it to Aegis 7.
Just before Kendra lifts off, the Hive Mind rises out of the crater and kills her, turning its attention to Isaac after she's dead. He defeats the Hive Mind, and manages to lift off the planet just as the large meteor enters the atmosphere. Isaac, distressed and disheartened at the loss of Nicole, watches the message again, but this time turns off her message before it shows her death.
At the sound of a small noise, Isaac turns and is attacked by a Necromorph looking disturbingly like Nicole. Whether this was another hallucination or a real Necromorph remains unknown - along with Isaac's fate.
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