Melatonin exhibits a wide variety of biological activity including antioxidant and anti-inflammatory effects. We have previously reported its protective effect on hepatic oxidative hepatic injury in burns. In this study, we investigated the role of nuclear factor kappa B (NF-κB) in melatonin-mediated protection against liver injury by using the burned-rat model. Melatonin (N-acetyl-5-methoxytriptamin, 10mg/kg (-1), i.p.) was administered immediately and 12 hours after thermal skin injury. Hepatic NF-κB expression was determined by Western blotting. TNF-α level in liver homogenate was quantified using enzyme-linked immunosorbent assay (ELISA) kit. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were determined to assess liver injury at the 24th hour after burns. Thermal skin injury caused significant elevation of hepatic NF-κB expression by 48 percent, TNF-α level by 55 percent and plasma AST and ALT activities by 2- and 3-fold, respectively, in comparison with normal control rats. Treatment with melatonin decreased significantly elevated hepatic NF-κB activity and TNF-α, maintaining the levels close to the control values Melatonin suppressed the elevation of plasma AST and ALT activities (p less than 0.001), which remained significantly increased compared to controls. In conclusion, thermal skin injury causes hepatic NF-κB activation that may mediate the release of hepatic TNF-α and contribute to liver damage. Melatonin protects against burn-induced hepatic injury as to a certain extent this effect may result from the suppression of NF-κB-mediated inflammatory response.