Acetaminophen (AAP) is a commonly used analgesic and antipyretic drug; however, when used in high doses, it causes fulminant hepatic necrosis in both humans and experimental animals. In this study, we investigated whether selenium (Se) and N-acetylcysteine (NAC), alone or in combination, are protective against AAP toxicity in mice. At the beginning of the experiment, blood samples were taken from 10 of 350 mice. Then, the remaining mice were randomly allocated into four groups, each consisting of 35 animals. The 1st group received a sin-le administration of AAP by gavage at a dose of 600 mg/kg-bw, p.o. The 2nd group (AAP-Se) was treated with sodium selenite (0.5 mg Se/kg-bw, p.o.) one hour after ingestion of AAP. The 3rd group (AAP-NAC) ingested AAP, 1.5 h later followed by NAC (500 mg/kg-bw, p.o.). The 4th group (AAP-Se-NAC) was given sodium selenite and NAC, 1 and 1.5 h after administration of AAP, respectively. From each group, blood samples of seven mice for each time point were taken at 4, 8, 24, and 48 h after AAP toxicity. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) levels were measured. Compared with AAP group, the levels of ALT were lower after AAP ingestion in AAP-NAC, AAP-Se, and AAP-Se-NAC groups at the 8th hour. ALT, AST, and LDH levels in AAP-Se-NAC group were 50% of the levels of other groups starting form the 4th hour of toxicity. It is concluded that protection against AAP hepatotoxicity using a combination of Se and NAC is better than that found with either agent alone.