The gastric protective properties of the anti-ulcer drug, colloidal bismuth subcitrate (CBS; DE-NOL) were examined in comparison with the effects of prostaglandin E2 (PGE2), sucralfate and cimetidine using an ethanol induced gastric erosion model in rats. To elucidate the mechanism of action of CBS it was studied whether it could stimulate PGE2 generation in gastric mucosa. Using a quantitative visual scoring technique of mucosal damage, CBS was shown to be less potent than PGE2, though about 4 times more potent than sucralfate at reducing ethanol induced gastric lesions. Cimetidine was only weakly active. Pretreatment of rats with CBS led to complete, partial and no protection at 0.25, 8 and 16 hr respectively. Prostaglandin generation was stimulated by vortexing biopsies of washed fundus, and the released PGE2 was measured by radio-immuno assay. PGE2 generation was dose-dependently increased by oral doses of CBS. Peak synthesis occurred at 0.25 hr. Although partial protection against ethanol lesions was found 8 hr after administration, basal levels of PGE2 had already returned at 4 hr. Indomethacin blocked control and CBS stimulation of PGE2, but only partially blocked the protection against ethanol induced lesions. These findings indicated that CBS protects the rat gastric mucosa against ethanol lesions, and that both prostaglandin and non-prostaglandin mediated mechanisms are probably involved.