The antiulcer effects and protective mechanisms of cisapride, a prokinetic benzamide agonist of 5-HT3 and antagonist of 5-HT4 receptors, were investigated in gastric mucosal injury induced by pretreatment with 50% v/v ethanol in rats. The duration of the protective effect was also studied and the results were compared with those of 5-HT. 240 min after administration of cisapride (10, 25 and 50 mg/kg) the total area of gastric lesions decreased significantly, in macroscopical and histological evaluations, and the mucus, hexosamine, and sulphated glycoprotein content were significantly increased. Indomethacin partially reversed cisapride protection suggesting that the beneficial antiulcer effects of this drug could be mediated in part by prostaglandins. This study confirms that this benzamide, in this experimental model, enhances gastric PGE2 production. We also investigated the time course of action of 5-HT, 30-240 min before ethanol administration, and our study not only demonstrates the ulcerogenic action of the amine (30 min of pretreatment) but also its protective nature, shown macroscopic and microscopically, after 240 min of its administration, without any effect on PGs production. These findings suggest a new gastroprotective feature of cisapride partly explained through a prostaglandin-dependent mechanism and possibly independent of its 5-HT activity.