Nonsteroidal antiinflammatory drugs such as aspirin and indomethacin are known to induce gastric mucosal damage including bleeding, ulceration, and perforation in humans and animals. Although it has been proposed that a deficiency of endogenous prostaglandins due to inhibition of cyclooxygenase by the drug is involved in these effects, the exact pathogenic mechanism remains to be elucidated. It has recently been proposed that neutrophil- and oxygen radical-dependent microvascular injuries may be important prime events that lead to mucosal injury induced by nonsteroidal antiinflammatory drugs. Lipid peroxidation mediated by oxygen radicals, especially hydroxyl radicals, plays a crucial role in the development of the gastric mucosal injury induced by indomethacin. Both allopurinol, an inhibitor of xanthine oxidase, and neutrophil depletion by intraperitoneal injection of antineutrophil antibody significantly attenuates indomethacin-induced gastric injury. In this paper, we have reviewed the recent data that assess the role of oxygen radical and lipid peroxidation in the pathogenesis of indomethacin-induced gastric mucosal injury in rats and humans.