Background: The sterile inflammatory response is one of the key mechanisms leading to hepatic ischemia-reperfusion injury. Melatonin has been shown to prevent organ injuries, but its roles in the inflammatory response after hepatic ischemia-reperfusion injury have not been fully explored, especially in late ischemia-reperfusion injury. The present study aimed to investigate the roles and possible mech- anisms of melatonin in the inflammatory response after hepatic ischemia-reperfusion injury.Methods: Sixty Sprague-Dawley rats were randomly divided into a sham group, ischemia-reperfusion injury group (I/R group), and melatonin-treated group (M + I/R group). The rats in the I/R group were subjected to 70％ hepatic ischemia for 45 min, followed by 5 or 24 h of reperfusion. The rats in the M + I/R group were injected with melatonin (10 mg/kg, intravenous injection) 15 min prior to ischemia and immediately before reperfusion. Serum and samples of ischemic liver lobes were harvested for future analysis, and the 7-day survival rate was assessed after hepatic ischemia-reperfusion surgery. Results: In comparison with the I/R group, the M + I/R group showed markedly decreased expression levels of inflammatory cytokines (IL-6 and TNF- α) and numbers of apoptotic hepatocytes ( P < 0.05). Immunoblotting showed that the expression levels of IL-6, p-NF- κBp65/t-NF- κBp65 and p-I κB- α/t-I κB- α in the M + I/R group were significantly lower than those in the I/R group, and immunofluorescence staining showed that the expression level of p-NF- κBp65 in the M + I/R group was lower than that in the I/R group ( P < 0.05). The 7-day survival rates were 20％ in the I/R group and 50％ in the M + I/R group ( P < 0.05). Conclusions: Melatonin downregulated the activity of the NF- κB signaling pathway in the early and late stages of hepatic ischemia-reperfusion injury, alleviated the inflammatory response, protected the liver from ischemia-reperfusion injury, and increased the survival rate.