This study was designed to compare the gastroprotective effects of colloidal bismuth subcitrate (CBS) with those of sucralfate and methylated analog of prostaglandin E2 (PGE2) against acute gastric lesions induced by absolute ethanol, acidified aspirin (ASA), and water immersion and restraint stress in rats. When given orally, both CBS and sucralfate prevented in a dose-dependent way the formation of gastric lesions induced by all three ulcerogens, CBS being about 7, 2, and 20 times more potent, respectively on a weight-to-weight basis than sucralfate. Methylated PGE2 was also highly effective against these ulcerogens. Bismuth subnitrate was ineffective against acute gastric lesions induced by stress conditions. The protection of both CBS and sucralfate was reversible when the animals were pretreated with indomethacin to suppress the generation of endogenous prostaglandins. Since CBS and sucralfate increased the production of PGE2 in the gastric mucosa, we postulate that their gastric protective action may be mediated, at least partly, by mucosal prostaglandins.