Our narrator, Dominick Birdsey, has a twin brother, Thomas. How can you tell them apart? It's easy: Thomas is the one ranting about Communists out to get him and Dominick is the one with anger-management issues. Also, Thomas only has one hand, since he chops the other one off in the middle of a library as a warning to America to stop its warmongering ways.
And that's just the first chapter of I Know This Much is True. Since a library is a place of quiet and knowledge, not self-dismemberment, Thomas is declared a danger and sent to the Hatch Forensic Institute, a mental hospital. Dominick wants him out, so he works with Thomas's social worker, Lisa Sheffer, and doctor, Dr. Patel, to find a way to release his brother.
This incident prompts a lot of self-reflection in Dominick. He thinks back to growing up in the late 1950s/early 60s with his brother, his Ma (who is now dead of breast cancer), and Ray, his stepdad. He and Thomas never knew who their real father was, and Ray was often abusive, taping Thomas's hands together or pretending he was Harry Potter and locking him in a cupboard under the stairs.
When he's not trying to trace back to the beginning of Thomas's illness—Was it when Dominick refused to be his roommate in college? Or when Ray threw Thomas down the stairs after catching him and Ma having a tea party?—he's trying to deal with other problems in the present. His girlfriend, Joy, isn't bringing any joy to his life. She's pregnant, even though Dominick had a vasectomy years ago, and she insists the baby is his, and adding to his misery is the fact that Dominick still isn't over Dessa, his first wife, either.
Dominick and Dessa divorced after losing their child, a loss Dominick never wanted to go through that again (hence the snip-snip). And he's trying to find time to actually earn a living as a housepainter.
His one client, Henry Rood, shoots himself while Dominick is fixing the shutters, and Dominick sees the whole thing. He's so startled, he falls off the roof and ends up in the hospital. While he's there, not only does Joy leave him (she admits the baby isn't his), but his roommate's fiancé recognizes Dominick, and she has a present for him. It turns out she's the woman he paid years ago to translate his grandfather's life story from Italian. She disappeared, but now she's back. (No, Grandpa's story isn't called deus ex machine.)
Here's the story of Domenico Tempesta, Dominick's grandfather: He is a prideful, arrogant man who came over from Italy near the turn of the 20th century with his two brothers. One brother is killed when he's caught having an affair with a cop's wife, and the other dies after falling off the roof (sounds familiar) in an accident Domenico feels responsible for.
Domenico bargains for a wife, Ignazia, and gets her monkey-looking cousin Prosperine in the deal. Ignazia swears she's a virgin, but she ends up having two children soon after they're wed—a black-haired boy, dead on arrival, and a red-haired girl with a harelip (Dominick's Ma). Domenico is furious, believing she was somehow impregnated by two different men.
One night, Prosperine tells Domenico that she and Ignazia aren't who they say they are. They're like Italian Thelmas and Louises, on the run after killing Ignazia's abusive husband in their home country. This frightens Domenico, and he's afraid they'll kill him next. However, the local priest convinces him to forgive his wife's past sins and love her for her good qualities. (Like her cooking, and her general acceptance of being beaten by her husband)
Things go downhill, as they do, and they resume fighting soon enough. The women try to run away with Concettina, Domenico's daughter, but he intercepts them at the train station and brings them home. Except Prosperine—he leaves that monkey-faced hag on the Express to Whereverville.
However, then one day, Domenico catches his wife in bed with Prosperine. She runs, and Domenico tracks her to a shack near a lake. He has her arrested and committed to a mental health institution, but later, his wife kills herself in the same lake. His daughter survives, and thus ends Domenico's long, tragic tale.
Back in the present, Dominick is grappling with his own anger-management issues and his martyr complex over being his brother's keeper. He manages to blackmail the hospital into releasing Thomas (a guard kicked Dominick in the balls way back in Chapter 2, and he had a doctor record the whole incident) and gets him placed in a safe house.
Bad idea: Thomas escapes that night. He hasn't even been free twenty-four hours before killing himself, jumping off the Falls into the river. Dominick arranges the funeral and yells at Ray at the after-party (or whatever you call the gathering after a funeral), finally fed up with how much Ray abused Thomas as a child.
Dominick slips into a deep depression, even considering suicide himself, but Dr. Patel convinces him to keep moving forward. Joy arrives with her stupidly named baby, Tyffanie, and tells Dominick she's HIV positive. He gets checked, and comes up negative. Phew.
Ray gets his leg amputated because of diabetes, and Dominick now has to take care of him, but he doesn't seem to mind. Ray tells Dominick who his real father is: Henry Drinkwater, a Wequonnoc Indian, which means that Dominick is the cousin of Ralph Drinkwater, a guy he went to school with who works as a janitor at the hospital which housed Thomas. It also means that Dominick is a millionaire, cashing in on his Native American heritage as though it's been a part of him all along, when they build a casino.
Thomas's death turns out to be the best thing ever. Dessa remarries Dominick. Joy dies, and her death also benefits Dominick because he gets to adopt her unfortunately named baby. He returns to teaching, makes amends with his stepfather, and lives happily ever after. The end.