Hemorrhagic lesions in the small intestinal mucosa have been demonstrated in humans and experimental animals following hemorrhagic shock and intestinal ischemia. In order to define the role of superoxide radicals and xanthine oxidase in the pathogenesis of the mucosal lesions, we compared the microscopic mucosal changes produced by 3 h of regional hypotension (intestinal arterial pressure = 30 mmHg) in untreated cats and cats pretreated with either superoxide dismutase or allopurinol. In the untreated animals the mucosa was characterized by massive epithelial lifting down the sides of the villi, completely denuded villi, and most frequently by disintegration of the lamina propria, hemorrhage, and ulceration. Pretreatment with either superoxide dismutase or allopurinol significantly attenuated the necrosis of villus and crypt epithelium produced by 3 h of ischemia. The results of this study suggest that superoxide radicals are involved in the pathogenesis of ischemic mucosal lesions and that the enzyme xanthine oxidase is the source of superoxide radicals in the ischemic small bowel.