Pyrazole treatment to induce CYP2E1 was recently shown to cause liver injury in ob/ob mice but not in lean mice. The current study investigated the effects of S-Adenosyl-L-methionine (SAM) on the CYP2E1 dependent liver injury in ob/ob mice. Pyrazole treatment of ob/ob mice for two days caused necrosis, steatosis, elevated serum transaminase and triglyceride levels compared to saline ob/ob mice. Administration of SAM (50 mg i.p./kg body weight every 12 h for 3 days) prevented the observed pathological changes as well as the increase of apoptotic hepatocytes, caspase 3 activity and serum TNF- levels. SAM administration inhibited CYP2E1 activity but not CYP2E1 content. The pyrazole treatment increased lipid peroxidation, 4-hydroxynonenal and 3-nitrotyrosine protein adducts and protein carbonyls. These increases in oxidative and nitrosative stress were prevented by SAM. Treatment of ob/ob mice with pyrazole lowered the endogenous SAM levels and these were elevated after SAM administration. Mitochondrial GSH levels were very low after pyrazole treatment of the ob/ob mice and this was associated with elevated levels of malondialdehyde and 4-hydroxynonenal and 3-nitrotyrosine protein adducts in the mitochondria. All these changes were prevented with SAM administration. SAM protected against pyrazole induced increase in serum transaminases, necrosis, triglyceride levels, caspase-3 activity and lipid peroxidation even when administered one day after pyrazole treatment. In the absence of pyrazole, SAM lowered the slightly elevated serum transaminases, triglyceride levels, caspase-3 activity and lipid peroxidation in obese mice. In conclusion, SAM protects against and can also reverse or correct CYP2E1-induced liver damage in ob/ob mice.