- An announcement that plays in the Spaceflight Terminal states that "over 5,000 people currently live and work" on Sevastopol. However, The Art of Alien: Isolation states that the station has a maximum capacity of around 3,000 inhabitants, with only 500 on board at the time the game's events begin.
- Just before Axel is killed, the Xenomorph's drool lands on his shoulder, implying the creature is above him. However, when it attacks, it impales him from behind before dragging him through a vent in the wall nearby.
- When the player first enters Seegson Communications, they witness a Working Joe murdering Hughes by bludgeoning his head against a wall, splattering the surface with his blood, more of which pools around his corpse on the floor. When Ripley returns to the area much later in the game, Hughes' corpse and the blood will be gone. While it is conceivable his corpse may have been taken away, it seems unlikely anyone would also take the time to clear up the blood.
- The Pilot's chamber aboard the derelict ship on LV-426 is far larger than it was in Alien. The walls are also further from the central platform and feature openings that were not present in the film, most obviously the one through which Marlow passes to deactivate the beacon.
- The melted hole that Kane used to access the derelict's cargo hold is located behind the Pilot's chair in the game. In the film, it was located to the chair's left.
- The Eggs in the derelict's cargo hold are grouped into large recesses separated by raised, walkway-like ridges. In the game, each of these recesses is covered in blue mist, but in the film, only one of the recesses is filled with this mist (although it could be argued this was due to budget/effects limitations in the film).
- Despite the fact the Anesidora crew apparently explore the exact same area of the cargo hold as Kane, there is no sign of the single open Egg that should remain from when he was attacked.
- Sinclair signs his penultimate archive log with the name Jake, yet his ID tag, found nearby, gives his first initial as "F".
- Whenever a Seegson Security officer is headbitten by a Xenomorph in-game, their helmet and visor will remain intact.
- The flamethrower that Amanda Ripley uses aboard Sevastopol is almost identical in design to the Flame Thrower used by the crew of the Nostromo, yet the latter was supposedly a custom tool fabricated by Parker specifically to deal with the Alien; it seems highly unlikely the two would be so similar in appearance.
- The content of archive log 078 implies it should be an audio log; for instance, the sender asks the recipient, "Can you hear me?" However, it is actually a simple text log; in this context, asking the reader if they can "hear" the message makes no sense.
- The maps for the Lorenz SysTech Spire upper transit and Solomons Habitation Tower habitation decks in Amanda's journal during mission 17 are incorrectly labelled, the titles having been swapped between the two.
- Parker's character model lacks the beard he had in the film.
- Dallas' jacket lacks the laces on the sleeves that can be seen in the film, looking more like Parker's jacket.
- Lambert's corpse is in a different position to that of the original movie.
- Jones is completely absent from the DLC and Ripley does not collect him on the way out of the Nostromo.
- Several times in the book, Marlow's surname is mis-spelt Marlowe.
- Much like in the game, the Pilot's chamber aboard the derelict is far larger than it was in Alien, although in the book the difference is even more extreme than in the game; Marlow mentions that the Anesidora would fit into the space four times over.
- Waits mentions that no one has been up to the Gemini Exoplanet Solutions labs since they were shut down, yet Amanda finds three dead bodies there.
- When Amanda discovers the Working Joe massacre in the Colonial Marshal Bureau, the novel states that there are four bodies. However, immediately following this, it identifies one of them as Waits, before pointing out that Amanda does not recognize the other two, making for just three in total.
- A similar numerical discrepancy occurs shortly afterwards when Amanda catches up to Samuels in Seegson Synthetics. The books first states that Samuels is being confronted by two Working Joes, but after he kills one, the second disappears.
- After the reactor purge, Ricardo tells Amanda that he is going to Seegson Communications, much like he does in the game. However, Amanda later finds him subdued by a Facehugger in the Marshal Bureau, which would mean he never went anywhere.
- Many of the expanded character names revealed in the book do not match information given in the game. For instance, Lingard's first name is said to be Tirsyris in the novel, yet her ID card in the game bears the initial "K", while "Chief" Porter is given the initial "W" on his ID card (seemingly in reference to Alien: Isolation writer Will Porter), yet is named Dion in the book. Other characters given incompatible or erroneous names include Suzanne Archer, Ransome, Sinclair, Spedding and Turner. Most confusing of all is Ricardo, whose surname is given as Garcia in the novel, seemingly making him the same Garcia who is mentioned in archive logs and who appears in the tie-in prequel comic; however, Garcia is killed by the Drone in the comic before the events of the game even begin.
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