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As with Red vs. Blue, The Strangerhood features a cast of diverse characters, each skewed in different ways and to varying degrees. Their natures are summed up by the Omnipotent Voice in episode 2 when it booms "Silence, assorted stereotypes!". There are nine main characters, and a small number of supporting characters.
Sam is the straight man of the series, often serious in comparison to the other residents; he often describes the situations the residents find themselves in as being ridiculous. Wade, Sam's housemate, is a stereotypical stoner, with bloodshot eyes and memory problems, and is frequently confused by events. Dr Chalmers is an elderly, curmudgeonly intellectual, frequently irritated by his fellow residents. Tovar is a confused ethnic minority, with a silly accent and a penchant for doing foolish things. Dutchmiller is a yuppie stereotype, enthusiastic about everything alternative. Catherine is a stereotypical dumb blonde, who uses other people to her own ends. Nikki is a teenager who is curious as to what is actually going on. Griggs is a stereotypical "tough guy" with camouflage facepaint and a highly aggressive attitude, and is Nikki's biological father in the present time.
- The Omnipotent Voice: A mysterious voice that can project itself through various devices and objects such as computers and newspapers and who orders the residents about.
- Evil Tovar/Tobar: Tovar's evil twin, created by accident. He is "pure evil" while the other Tovar is "pure moron."
- The Garden Gnome: A garden gnome that follows Griggs around and talks to him in an unintelligible language.
- Sam: A man who lives in isolation underground throughout the series and is the real Omnipotent Voice. Strangerhood Sam stole his name along with his labeled underwear.
- In Episode Six "Idol Desperation", Sam calls a number of characters on the telephone to tell them about Nikki. At first, it is the main characters, then moving onto other characters from the sim world, such as the Grim Reaper, the Social Bunny, and some objects such as the gnome and the pink flamingo.