Detective Joe Miller (Peter Krause) — A Pittsburgh detective who stumbles upon the existence of the Room. When his daughter becomes lost inside the Room, Joe sets out to get her back by using the Key to track down other Objects.
Anna Miller (Elle Fanning) — Joe's 8-year-old daughter. Her disappearance is seen by others as a probable family abduction by Joe in an ongoing child custody battle with his (unseen) ex-wife, Vanessa.
Detective Lou Destefano (Chris Bauer) — Joe's partner, whose murder in the story is blamed on Joe.
Detective Lee Bridgewater (April Grace) — Joe's friend at the police department. She is trying to clear Joe's name, and in so doing slowly discovers the powers held by the Room and its Objects.
Dr. Martin Ruber (Dennis Christopher) — A forensic scientist who works with Joe and who becomes obsessed with the Objects, going as far as killing in an attempt to get the Key. Through his obsession, he learns of and joins the Order of the Reunification, a cabal that believes the Objects are pieces of God and will allow direct communication with God if reunited as they were at the time of the Event. By the end of the series, Ruber believes he has become the Prophet of the Objects after having a vision (possibly a hallucination caused by dehydration) while staring at the Polaroid Object.
Jennifer Bloom (Julianna Margulies) — A member of the Legion, another cabal dedicated to finding all of the Objects and destroying them for the protection of humanity. Jennifer tries to warn Joe of the inherent danger of the Room and the Objects therein. Her brother, Drew, became obsessed with the Objects, and Jennifer believes that something in Room 9 of the Motel "destroyed" him
Karl Kreutzfeld (Kevin Pollak) — A wealthy ex-Legionnaire and collector of Objects. He owns a chain of dry-cleaning stores and a pawnshop that he uses to acquire Objects. Kreutzfeld claims to be searching for the Glass Eye to cure his son Isaac's leukemia. Alternately an ally and an enemy to Joe.
Wally Jabrowski (Peter Jacobson) — A man who has the Bus Ticket and is effectively a drifter. He has extensive knowledge about the Objects and their history.
Harold Stritzke (Ewen Bremner) — A voyeur who inherited the Comb from his aunt. He has become very paranoid after being pursued by the Order and others who want his Object for themselves.
Howard "The Weasel" Montague (Roger Bart) — A former philosophy professor turned small-time criminal. He's an obsessed collector of Objects who charts the Objects' relations to one another and introduces the idea of the Prime Object.
Milton Vrang (Chris McCarty) — A former member of a Cabal and only living burn victim of the Pen. He provides valuable and secret information to Dr. Martin Ruber on the mysterious and dangerous world of Objects and Object Seekers.
Suzie Kang (Margaret Cho) — A tough, chain-smoking, independent operator who works as an Object locator, selling information about the locations of the Room's Objects. She never touches them, as she recognizes the dangers that the Objects carry. Suzie runs her Object-tracking business out of the back of her mother's dry-cleaning business.
The Sood (Jason Antoon) — A seedy, Las Vegas-based dealer of Object "Science" – pictures, videos, and artifacts relating to Objects – but never Objects themselves.
The Occupant, formerly Eddie McCleister (Tim Guinee) — The Occupant was removed from time and space during The Event that made the Lost Room, leaving only his personal belongings as "Objects". Eddie no longer exists in time and there is no memory of his ever doing so, as even his wife has no recollection of him. He resides in a sanitarium under the name "John Doe" until found by Joe.
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