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Dead Space takes place in the 26th century. The USG Ishimura "Planet Cracker" ship, during the process of mining the planet of Aegis VII, sends out a distress signal to the Concordance Extraction Corporation (CEC); the CEC dispatches the USG Kellion to investigate. As the Kellion attempts to dock with the Ishimura, a malfunction occurs and the Kellion is badly damaged, and the crew begins to seek a means of return. As the crew explores the apparently abandoned Ishimura, they are attacked by grotesque monsters, who kill off all but Clarke, Hammond, and Daniels. Hammond recognizes that many of the ship's systems are failing, threatening the ship due to a nearby asteroid belt, and sends Clarke around the ship to fix the core systems to keep them alive.

During these treks, Clarke discovers various text and audio logs scattered throughout the ship and pieces together the events that transpired before his arrival: the ship's captain was actually an agent of the "Church of Unitology" — a large and influential religious cult — assigned to retrieve his religion's most deified relic, known as "The Marker", from Aegis VII, under the guise of an illegal mining operation; the planet itself had already been deemed by the Earth government as off-limits. Soon after the Marker was extracted and brought to the Ishimura, the civilians — first on the planet-side colony, then the ship — suffered from mass hysteria brought on by violent hallucinations, before subsequently killing each other. The captain cuts off traffic and communications between the two sides and later goes insane as well, prompting Dr. Terrance Kyne, the Chief Science Officer, to relieve him of duty, only to accidentally kill him in a struggle. An alien organism then began ravaging the colony, infecting the bodies of the dead and turning them into "Necromorphs" - mindless abominations that kill to spread the infestation. It then spread to the Ishimura via a colony shuttle that crashes into the docking bay, carrying several Necromorphs on board. Though Hammond states that he is unaware of what the Marker is, Daniels confides to Clarke that she believes Hammond is lying. Clarke would later encounter his girlfriend Nicole, one of the Ishimura's crew, though they are unable to meet directly.

With the critical systems repaired, the three are able to launch a beacon, attracting a nearby military ship, the USM Valor. However, the Valor, having picked up an escape pod launched by Hammond containing a Necromorph, becomes overrun and crashes into the ship. Hammond then deduces — from the heavy military equipment he finds on board — that the Valor was actually assigned to destroy the Ishimura. The group thus decides that they must find a shuttle and escape while they can. Clarke and Hammond then retrieve the vessel's power core in order to repair an available shuttle, but Hammond is killed by a Necromorph in the process. A surviving Dr. Kyne later contacts Clarke and urges him to return the Marker to Aegis VII, believing that it was a means of restraining the Hive Mind that controls the Necromorph. After assisting Clarke in loading the Marker onto the shuttle, Kyne is murdered by Daniels, who reveals her position as a government operative ordered to retrieve the Marker for her superiors. She further reveals that the Marker is a reverse-engineered copy of an artifact found on Earth, and was placed on Aegis VII by the government to monitor its effects. She then leaves on the shuttle without Clarke, but Nicole arrives and is able to help him recall it, prompting Daniels to flee via an escape pod.

Clarke takes the shuttle with the Marker to the colony, and replaces it there; this pacifies the Hive Mind, but also disrupts the gravity tethers holding a large continent-sized portion of the planet several miles off the surface, threatening to destroy the colony. As Clarke attempts to escape, Daniels appears and takes the Marker back to the shuttle, and shows Clarke (through a fully recovered distress transmission) that Nicole actually committed suicide before they arrived on the Ishimura, and Clarke's visions of her had been the Marker's way of attempting to bring itself back to the planet. Before she can leave, Daniels is killed by the gigantic Hive Mind, but Clarke is able to defeat it. Leaving the Marker behind, Clarke flies off in the shuttle before the colony is destroyed. As he sets course away from Aegis VII, Clarke begins thinking about Nicole, and is suddenly attacked by what appears to be Nicole in Necromorph form. The screen then cuts to black and the game ends, with Clarke's actual fate unclear.

Producer Glen Schofield revealed in an interview that Isaac is not dead, meaning that Isaac either survived the encounter, or it was a hallucination.

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      Video Memory: 256MB (nVidia GeForce 6800/ATI Radeon X1600 Pro (Shader 3.0 support)
      Sound Card: DirectX Compatible
      DirectX: 9.0c
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