Melatonin is a free radical scavenger and antioxidant. This indol is reported to efficiently scavenge both hydroxyl and peroxyl radicals and it also reduces both in vitro and in vivo tissue damage due to oxidants which generate oxygen toxic radicals. Lipopolysaccharide (LPS) administration induces oxidative damage in various tissues mainly due to its ability to increase reactive oxygen species. In the present work, we studied the morphological changes and lipid peroxidation in the Harderian gland after LPS administration and the effects of melatonin in preventing the induced changes. Hyperchromasia, vesicular degeneration, necrosis and infiltration with macrophages, monocytes and neutrophils were observed in the LPS-treated group (10 mg/kg, intraperitonally [i.p.]). Also, a typical structure of the glandular acini of the gland exhibited diffuse damage. In the LPS rats treated with melatonin (10 mg/kg, i.p.), a diminished number of infiltrative cells was seen, and cloudy swelling was reduced, as was nuclear hyperchromasia. Neither necrosis nor vesicular degeneration were noted in the melatonin-treated rats, and in general, glandular structure was preserved. Lipid peroxidation products increased significantly within six hours after LPS administration, and melatonin treatment decreased the LPS-dependent lipid peroxidation products. These data together suggest that melatonin protects the Harderian gland against LPS toxicity in terms of morphological damage.