The antiulcer effect of melatonin on gastric lesions caused by restraint-cold stress was studied with the intent of determining the mechanism of action of this agent. Melatonin dose-dependently prevented restraint-cold stress-induced gastric damage with around 90% inhibition at a dose of 60 mg/kg BW. When compared with already marketed antiulcer drugs such as ranitidine and omeprazole, melatonin was found to be more effective than ranitidine but less effective than omeprazole in preventing stress ulcer. As stress-induced gastric lesions are mainly caused by oxidative damage because of hydroxyl radicals (*OH), the effect of melatonin in scavenging the.OH generated during stress conditions in vivo as well as in an in vitro model system were studied. The results indicate that melatonin caused an 88% reduction of endogenous *OH during stress in vivo, an observation confirmed in an established in vitro system. Furthermore, a decrease in the activity of gastric peroxidase (GPO) and an increase in the gastric mitochondrial superoxide dismutase (Mn-SOD) activity because of restraint-cold stress was attenuated by melatonin pretreatment indicating that the indole possibly exerts its gastroprotective effects through its direct as well as indirect antioxidant activities. Moreover, in separate experiments, cotreatment of rats with melatonin and ranitidine or omeprazole was found to protect against stress ulceration in doses at which either of these alone could not protect the stomach. The findings raise the possibility of melatonin being considered as an effective gastroprotective agent individually or as a cotreatment with either ranitidine and omeprazole.