Rebamipide, a novel antiulcer agent, has been shown to protect against gastric injury by free radicals. The effect of rebamipide was examined using two rat models of mucosal injury: the stomach was exposed to luminal perfusion of 10 mM H2O2 for 10 min or to local ischemia for 30 min. The effect of deferoxamine, a chelator of Fe3+, was also evaluated to determine whether Fe3+-mediated production of hydroxyl radicals contributed to the damage induced by H2O2. The pylorus was ligated and a double-lumen cannula was inserted into the forestomach for luminal perfusion. [51Cr]EDTA was administered intravenously and mucosal integrity was monitored by measuring blood-to-lumen [51Cr]EDTA clearance. Rebamipide reduced the increase in EDTA clearance induced by ischemia or H2O2. Furthermore, deferoxamine attenuated the H2O2-induced increase. These results suggest that rebamipide has a protective effect against oxygen radical-mediated gastric damage and that Fe3+ is involved in the H2O2-induced injury.