Cholestyramine, a bile-binding agent, markedly inhibited the development of gastric lesions induced by water-immersion stress in rats and of gastric and intestinal lesions induced by indomethacin in rats and dogs with an intact pylorus. However, cholestyramine had no effect on gastric lesions induced by stress in pylorus-ligated rats and on aspirin-induced gastric lesions in rats and dogs with or without pylorus ligation. Hydrotalcite, a potent antacid, significantly inhibited the gastric lesions induced by stress and aspirin in rats and dogs with or without pylorus ligation. Hydrotalcite also inhibited the gastric lesions induced by a single administration of indomethacin in rats with an intact pylorus. In contrast, the agent had no effect on gastric and intestinal lesions induced by repeated administration of indomethacin to rats and dogs with an intact pylorus. These results suggest that while bile probably plays an important role in the pathogenesis of stress-induced gastric lesions and of indomethacin-induced gastric and intestinal lesions, bile does not appear to play a role in the pathogenesis of aspirin-induced gastric lesions.