The main cast of the miniseries "I Know This Much Is True" includes:
- Mark Ruffalo as Dominick and Thomas Birdsey (dual role)
- Melissa Leo as Ma, the mother of Dominick and Thomas
- John Procaccino as Ray Birdsey, the stepfather
- Rob Huebel as Leo, Dominick's best friend
- Michael Greyeyes as Ralph Drinkwater, a former classmate
- Juliette Lewis as Nedra Frank, a grad student
- Kathryn Hahn as Dessa Constantine, Dominick's ex-wife
- Rosie O'Donnell as Lisa Sheffer, a social worker
- Imogen Poots as Joy Hanks, Dominick's live-in girlfriend
- Archie Panjabi as Dr. Patel, Thomas's psychologist
- Bruce Greenwood as Dr. Hume
- Marcello Fonte as Domenico Tempesta, the maternal grandfather
There are also younger actors for the younger versions of key characters and a recurring supporting cast.
