Mepirozole, a basic antiinflammatory drug and duodenal ulcerogen in laboratory animals, macroscopically protected the gastric mucosa of rats from HCl-ethanol-induced damage in a dose-dependent manner. These effects were evident when the agent was given orally, intraperitoneally, or subcutaneously at 3 or 10 mg/kg 0.5 hr before HCl-ethanol administration. Histologically, the surface epithelial and pit cells were not protected by mepirizole, but most of the mucosal cells located in the deeper portions were well preserved. Gastric acid secretion in the pylorus-ligated or acute fistula preparation was not affected by 10 mg/kg of mepirizole. Gastric motility determined by a balloon method was dose-dependently inhibited by the agent. Mepirizole protection was significantly reduced by pretreatment with subcutaneous indomethacin (5 mg/kg) and N-ethylmaleimide (10 mg/kg). The gastric motility inhibited by mepirizole was not reversed by indomethacin and N-ethylmaleimide treatment. These results suggest that the mechanism underlying mepirizole protection relates to both endogenous prostaglandins and sulfhydryl compounds present in the gastric mucosa, but does not relate to an inhibition of gastric motility. Dulcerozine and other basic antiinflammatory drugs (tiaramide, tinoridine, and benzydamine) given either orally or intraperitoneally at 10-100 mg/kg also dose-dependently prevented the development of HCl-ethanol-induced lesions. Mepirizole and other basic antiinflammatory drugs are cytoprotective in the rat stomach.