Acetaminophen (APAP) is a popular over the counter medication for treatment of pain and fever. APAP is relatively safe when taken at the recommended dose. However, in excessive doses, it is associated with hepatic toxicity. The purpose of the present study was to examine the protective effect of SAMe when administered after APAP. The rationale for these studies was to evaluate the effectiveness of SAMe when administered after APAP dosage in order to model what occurs in the clinical setting. A second goal of this study was to compare the potency of SAMe to N-acetylcysteine (NAC), the current treatment for APAP toxicity. Male C57BL/6 (16-25 g) mice were used in all studies. Each treatment contained an n = 5 animals/group. The mice were randomly divided into 6 groups: vehicle (VEH), APAP, SAMe, SAMe plus APAP (SAMe+APAP), NAC and NAC plus APAP (NAC+APAP). The animals were injected intraperitoneal (ip) with 250mg/kg APAP or water. One hr later, SAMe and SAMe+APAP groups were injected (ip) with 1.25 mmol/kg SAMe. One hr after APAP or VEH injection, NAC and NAC+APAP groups were injected (ip) with 1.25 mmol/kg NAC. Hepatic toxicity was assessed 4 h after APAP injection by monitoring hepatic glutathione (GSH) levels, changes in alanine aminotransferase (ALT) levels, lipid peroxidation, liver to body weight ratios and examination of hepatic tissue under light microscopy. Normal liver function was noted in the VEH, SAMe and NAC groups. Hepatic toxicity was apparent within 4 h in the APAP treated groups SAMe protected the liver from APAP-induced damage as the SAMe+APAP group had lower ALT values when compared to the APAP group. SAMe+APAP mice also had less induction of lipid peroxidation and higher hepatic glutathione levels than the APAP group. Evaluation of hepatic tissue under light microscopy showed extensive centrilobular necrosis in the APAP group and only mild hepatic changes in the SAMe+APAP group. NAC treatment 1 h after APAP (NAC+APAP) reduced APAP hepatic toxicity. Plasma ALT values and histology supported a finding of NAC attenuation of APAP toxicity. Further studies investigated the protective effects of SAMe against APAP-induced hepatotoxicity on 4-hydroxynonenal (4HNE) adducted proteins and protein carbonyls. The results of this study have found that SAMe protects the liver from production of protein carbonyls and 4HNE adducts. In summary, APAP hepatic toxicity occurs within 1 h after injection in mice. SAMe administered 1 h after APAP was successful at reducing APAP hepatic toxicity. SAMe administered 1 h after APAP also reduced the extent of oxidative stress associated with APAP.