The Laeta Kalogridis-scripted adaptation of the Dennis Lehane novel is set to begin production in March for Paramount and Columbia.
While Lehane's contemporary, blue collar stylings have spawned feature adaptations like "Mystic River" and "Gone Baby Gone", "Shutter Island" was a dramatic change of pace.
Set in 1954, the twisty mystery focuses on a U.S. Marshall (DiCaprio) who finds himself investigating the disappearance of a patient at a hospital for the criminal insane in the midst of a hurricane.
Ruffalo will play DiCaprio's more experienced partner in the "Key Largo" meets "One Flew Over the Cuckoo's Nest" drama.
Although Ruffalo's recent "Reservation Road" vanished without a trace, the "Zodiac" and "Just Like Heaven" star has Fernando Meirelles' "Blindness" and Rian Johnson's "The Brothers Bloom" set for release next year.