In this study the role of free radicals and lipid peroxidation as mediators of chemically induced mucosal damage was investigated. Two enzymatic antioxidants, superoxide dismutase or catalase injected intravenously, reduced mucosal damage either by ethanol or aspirin. Of six nonenzymatic antioxidants, given in a wide dose range subcutaneously 30 min before intragastric administration of absolute ethanol, only propyl gallate decreased mucosal damage, while four of the antioxidants tested against aspirin were protective. These nonenzymatic antioxidants were antisecretory in the pylorus-ligated rat. The concentration of conjugated dienes and malondialdehyde measured in the gastric mucosa shortly after ethanol or aspirin administration remained unchanged or slightly decreased. These results indicate that free radicals may be involved in the pathogenesis of acute gastric mucosal injury caused by chemicals, but their mechanisms of action probably does not involve lipid peroxidation.