The ameliorating effects of melatonin and vitamin C plus vitamin E were examined histologically and biochemically in lung tissues in rats exposed to chlorpyriphos-ethyl (CE). Experimental groups were as follows: Control group (C), CE treated group (CE), vitamin C plus vitamin E treated group (Vit), melatonin treated group (Mel), vitamin C plus vitamin E plus CE treated group (Vit+CE), and melatonin plus CE treated group (Mel+CE). Vitamin E and vitamin C were administered intramuscularly at the rates of 150 and 200 mg per kg body weight, respectively, in Vit and Vit+CE groups, once a day for 6 consecutive days. Melatonin was administered intramuscularly at the rate of 10 mg per kg body weight in Mel and Mel+CE groups, once a day for 6 consecutive days. At the end of the fifth day, the rats of CE, Vit+CE and Mel+CE groups were treated orally with CE dissolved in corn oil with two equal doses of 41 mg CE per kg body weight at zero and twenty-first hours. Tissue samples of lungs were taken by using appropriate techniques for biochemical and histological examinations under anesthesia at the twenty-fourth hours of CE administration, at the end of the sixth day of the experiment. In tissue homogenates, the level of thiobarbituric acid reactive substances (TBARS), antioxidant potential (AOP), and the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were determined. TBARS was significantly high (p < 0.05) in CE group compared to control group, while TBARS was found to significantly decrease (p<0.05) with Vit and Mel groups compared to control. On the other hand, TBARS was seen to significantly decrease (p<0.05) in both groups of Vit+CE and Mel+CE compared to CE group. In comparison with CE group, SOD activity was significantly high (p<0.05) with the groups of Vit, Mel, Vit+CE and Mel+CE. GSH-Px activity was found to significantly decrease (p < 0.05) with CE group, compared with both C and Vit groups. AOP was significantly lower (p<0.01) in CE group than C group. Although there was an increased AOP with Vit+CE and Mel+CE groups compared to CE group, the increase in AOP was only seen to be significant (p<0.05) in Mel+CE group. In comparison with C group, AOP significantly (p < 0.05) increased with Vit group. There was also a significant (p < 0.05) increase in AOP with Mel+CE group, compared with CE group. Additionally, AOP was significantly lower (p<0.05) in Vit+CE group than Mel+CE group. Lungs were examined histologically at the end of sixth day. There were remarkable changes in the histomorphology of peribronchial and perivascular area in the lung of rats treated with CE. These were infiltration of mononuclear cells (such as lymphocytes, plasmocytes, macrophages), hyperplasia of type II pneumocyte, and thickened and increased connective tissue. Damage to the lung tissue such as increased inflammatory mononuclear cells in peribronchial and perivascular areas were more pronounced for the CE group than Vit+CE and Mel+CE groups in which these changes were higher than C, Vit and Mel groups. These results suggest that CE increases lipid peroxidation and decreases antioxidant enzymes activities and AOP due to increasing oxidative stress induced by CE, and high doses of vitamin C plus vitamin E and melatonin considerably reduce CE toxicity in lung tissues of rats.