Cigarette smoking is common in societies worldwide and has been identified as injurious to human health. The current study was designed to investigate the protective effect of melatonin, a radical scavenger and antioxidant, on nicotine-induced oxidative stress and morphological changes in the lung and liver of the rats. Three groups of male rats (controls, nicotine-treated [0.5 mg/kg], and nicotine plus melatonin [10 mg/kg] were used in this study. Levels of lipid peroxidation (LPO) products, superoxide dismutase (SOD) and glutathione (GSH) activity were measured in the tissue homogenates. Immunohistochemical and histological changes were also examined. The results revealed an increase in LPO and decrease in both SOD and GSH activity in the lung and liver homogenates on nicotine-treated rats. Melatonin administration to nicotine-treated rats attenuated the increase in LPO products and restored the SOD activity and GSH levels. The immunohistochemical and histological examination demonstrated marked increase in the immunoreactivity of nitrotyrosine, a specific "footprint" of peroxynitrite, and tissue damage in the lung and liver of nicotine-administered animals. Again, melatonin treatment reduced both nitrotyrosine reactivity and tissue damage associated with nicotine administration. These results, along with previous observations, suggest that melatonin may be useful in combating free radical-induced oxidative stress and tissue injury that is a result of nicotine toxicity.