Reactive oxygen species (ROS) are involved in pathophysiology of ischemia/reperfusion injury. Melatonin is a potent scavenger of ROS. Thus, this study was designed to elucidate its effects in a combined hepatic warm ischemia and resection model. The right lateral and caudate lobes (32% of liver volume) of Sprague-Dawley rats underwent warm ischemia for 30 min followed by reperfusion and subsequent resection of the nonischemic liver tissue. Some rats were gavaged with 50 mg/kg melatonin 2 hr before the onset of experiments. Controls received the same volume of microcrystalline cellulose. Survival, transaminases, histology, flow cytometry, inducible nitric oxide synthase (iNOS) expression, and activation of signal transduction pathways [c-Jun N-terminal kinase (JNK), cJUN, IkappaB kinase alpha (IKKalpha), proliferating cell nuclear antigen (PCNA), and Ki67] were assessed for hepatic injury, oxidative stress, and cell proliferation. Melatonin significantly improved animal survival and decreased transaminase levels, the indices for necrosis, liver damage, leukocyte infiltration, and iNOS expression. In parallel, the expression of IKKalpha, JNK1, and cJUN decreased by 35-50% after melatonin (P < 0.05). At the same time, melatonin reduced the expression of both PCNA and Ki67 in liver (P < 0.05). Melatonin is hepatoprotective most likely via mechanisms including inhibition of IKK and JNK pathways and regulation of cell proliferation.