An 8-month-old, spayed female Shetland sheepdog presented 48 hours after ingesting acetaminophen (1 gm/kg body weight). On presentation, the dog was laterally recumbent and hypovolemic. The dog had brown mucous membranes, severe Heinz-body hemolytic anemia, bleeding tendencies, and a red blood cell (RBC) glutathione (GSH) concentration that was 10% of reference values, despite a regenerative erythroid response. Treatment with s-adenosyl-l-methionine (SAMe) as a GSH donor successfully rescued this dog, despite the animal's late presentation after drug ingestion. A loading dose (40 mg/kg body weight) of a stable SAMe salt per os was followed by a maintenance dose (20 mg/kg body weight) sid for 7 days. Additional therapeutic interventions included an intravenous (i.v.) infusion of one unit of packed RBCs (on admission), i.v. fluid support (3 days), and famotidine (7 days) to reduce gastric acidity. Sequential assessment of RBC GSH concentrations and RBC morphology documented response to antidote administration within 72 hours. This case suggests that SAMe may provide a therapeutic option for treatment of acetaminophen toxicosis in dogs capable of retaining an orally administered antidote and maintaining adequate hepatic function for metabolism of SAMe to its thiol substrates.