Oxygen-derived free radicals are cytotoxic and promote tissue damage. Dimethyl sulfoxide (DMSO) and allopurinol scavenge hydroxyl radicals, and the latter agent also inhibits the enzyme xanthine oxidase, which is responsible for the formation of superoxide anions. These agents were given daily by gavage (1 ml/d). After 2 days of administration as 1, 2, or 5% solutions, the H+output of the rat with or without pyloric ligation was not significantly affected.After six hours reserpine (5 mg/kg i.p.) or serotonin (50 mg/kg i.p.) produced ischemic mucosal injury in all stomachs (39 ± 5.2 mm2and 25.9 ± 2.8 mm2, mean ± standard error of the mean [SEM], n = 10). Pretreatment for 2 days with 1 ml/d of 1% allopurinol or DMSO significantly (p < 0.001) protected the rat against the reserpine (23 ± 2.1 mm2and 24 ± 1.9 mm2, respectively, vs 39 ± 5.2 mm2, n = 10) and serotonin injury (10 ± 1.5 mm2and 11 ± 1.8 mm2, respectively, vs 25.9 ± 2.8 mm2, n = 10). However, 2 days pretreatment with 1 ml/d of 2% allopurinol or DMSO was more effective (p < 0.001) in this respect, and injury only developed in 40% of the rats given reserpine (8 ± 1.2 mm2and 9 ± 1.6 mm2) and in 20% of those given serotonin (2.4 ± 0.4 mm2and 1.9 ± 0.5 mm2). Similar pretreatment with 5% solutions completely protected the rat stomach against the reserpine and serotonin injuries without significantly influencing the H+output.The similarity in efficacy between allopurinol and DMSO and the fact that scavenging oxyradicals is the only action they share suggests that oxygen-derived free radicals are directly implicated in the mechanism of development of ischemia-induced acute gastric mucosal injury and that scavenging these radicals protects against the injury without influencing acid secretion (ie, cytoprotection).