Misoprostol, a PGE₁ derivative that inhibits gastric acid secretion in rats, was compared with cimetidine and sucralfate in several rat experimental ulcer models. Gastric lesions were produced by aspirin, indomethacin, stress, sodium taurocholate, and ethanol. In all tests, misoprostol (50, 100, and 200 g/kg) and cimetidine and sucralfate (50, 100, and 200 mg/kg) were administered intragastrically. Misoprostol protected against gastric lesions in all five experimental ulcer models at lower than gastric antisecretory doses. Cimetidine protected in the indomethacin, aspirin, and stress models, but only at gastric antisecretory doses, and did not protect against lesion formation in the ethanol and taurocholate models. Sucralfate, over the dose range tested, was not consistently protective in any of the five experimental ulcer models. It is concluded that misoprostol provides gastric mucosal protection against a wide variety of noxious agents by means of a unique mechanism and that reduction of gastric acid secretion is not required, as it is with cimetidine, for the protective effect.