At the start of the game, Isaac is seen being questioned about the events that transpired on the USG Ishimura three years ago on a space station called The Sprawl. Upon being questioned, Isaac suddenly saw the visions of his dead girlfriend, Nicole and many of the other monstrosities that he saw aboard the Ishimura in Dead Space which causes him to black out. Isaac wakes up an unknown amount of time later to be informed by Franco, the protagonist of Dead Space: Ignition that he is in 'grave danger'. Franco was killed by an Infector, turning him into a Slasher. After making his way through the hospital section of The Sprawl and witnessing many of the horrors of the Necromorph attack, Isaac is contacted by Daina who informs Isaac that they need to meet because the dementia that he developed on Aegis VII will kill him.
After being interrogated on the events of the USG Ishimura, Isaac Clarke woke up in a straitjacket with Franco waking him. But, he was shaken awake when a Necromorph transformed Franco into a Slasher. Isaac is soon on the run again as multiple inmates of the asylum transformed into Necromorphs.
Narrowly escaping with his life, Isaac must find a way out of his straitjacket. He soon encountered the two security officers that immediately shoot at him, but they are killed and dragged into a ceiling vent by an unknown Necromorph. Isaac proceeds carefully as the bodies of the officers are thrown from the next air vent.
Isaac enters a room to find Foster Edgars who threatens to kill him, but soon releases Isaac from his restraints. He gives him a flashlight and a small Health Pack before violently slitting his own throat with a scalpel.
Isaac proceeds to a surgery room by taking an air duct route. There, he finds a Kinesis Module and some metal rods. Isaac is able to break out of the surgery room by smashing the windows with Kinesis and must subsequently defeat several Necromorphs by using only thrown objects.
Continuing through the Medical Bay, he finds a restrained Necromorph and a man in a surgical device. The man was about to be operated with a tissue cutter before the Necromorph outbreak. Isaac tries to free the man, but fails as a Necromorph enters the room and kills the man. Left with no choice, Isaac pulled the tissue cutter out and jury-rigs it with his flashlight to create a modified (And possibly better) Plasma Cutter and uses it to kill the Slasher.
Isaac met a man named Nolan Stross. He urges Isaac to follow him, but due to Stross having a head start, they get separated by a quarantine door that closes off as Isaac is about to enter. Stross tells Isaac to keep moving as the door closes. Meanwhile, Daina contacts Isaac and is horrified to learn that Isaac missed his opportunity to escape. Isaac argues that he doesn't need her help before being attacked by a horde of Necromorphs. Realizing that the situation is out of control, Isaac decides to accept Daina's instructions and she plots a new path for Isaac.
Isaac proceeds to a room which contains several Stasis beds. He hacks one of the beds and pulled the Stasis Module out within it, only to be immediately attacked by a Necromorph security guard. Fortunately, the hacked Stasis bed overloads and freezes the attacking Necromorph, giving Isaac enough time to finish it off.
Isaac found a Store where he changes into his old Engineering Suit, before proceeding to the marked area. He subsequently encounters a Tripod and is forced to fight it before heading up to another air duct.
- When Isaac is being questioned, you can see that a model of the "USG Ishimura" and a Rubix Cube with red markings are on the table in front of him. One of the ink blots in the Dementia Trailer can also be seen on the table.
- The Slasher that appears in the Triage Room can kill you in one hit, no matter how high is your health, what RIG you wear, and no matter how much it's upgraded. The Slasher is also invulnerable; after its initial stasis from hacking the machine, you must manually use Stasis again in order to kill it.
- In the room where you get the Plasma Cutter, you have infinite ammo in that room and that room only. Once you leave, you no longer have infinite ammo, even if you go back inside the room.
- According to John Calhoun, associate producer at Visceral Games, the faces and diagnostics of other Marker test subjects, in the Diagnostics Room, are all members of the UI development team.
- In the room where you get the Plasma Cutter, there will be a microscope on one of the counters in the center room. If you throw this at the man on the table, it will dismember him though he will strangely still talk and move as before.
- In the room where there is a lockdown with Stross, if you are quick to get around the corner you can see Stross fall through the floor.
- At one point as you are walking if you look on a counter you can see one of the ink blots from the dementia trailer.
- On some of the X-rays you can see the Visceral Games logo inside skulls.
- In the room where Isaac is freed by Edgar, on a nearby counter, there is an "Ishimura" Journal.
- In the room where Isaac gets his first suit, there is a weighing machine. If Isaac stands on it, the machine will indicate that Isaac weighs 195 pounds (almost 89 kg). When Isaac puts on his suit, he weighs 239 pounds. Also, if on New Game+ different suits will have different weights (e.g. Elite Engineering suit will cause you to weigh 255 pounds).
- When you enter the dark room right after you get the flashlight, if you look closely to the right, you can see in the table a drawing of an eye bleeding, foreshadowing what will happen in Chapter 13.
- The Tripod is encountered for the first time in this chapter.
- The Puker is introduced in this chapter.