The gastric and duodenal anti-ulcer activity of sulpiride, a dopamine D2 receptor antagonist, was studied on various types of experimentally induced ulcers in rats, viz., pylorus ligation and water immersion + restraint stress-induced gastric ulcers, gastric mucosal damage induced by nonsteroidal anti-inflammatory drugs and reserpine, and duodenal ulcers induced by cysteamine hydrochloride. It has been found to possess significant anti-ulcer activity against all these models. In 19 h pylorus ligated rats, it significantly reduced the gastric secretion, increased the fucose and sialic acid concentration of the gastric juice and reduced its protein content, thus increasing the total carbohydrate:protein (TC/PR) ratio. These results suggest that the antisecretory and gastric mucosal barrier strengthening effects of sulpiride may be responsible for its anti-ulcer activity. A central component also appears to be involved in its anti-ulcer action against water immersion + restraint stress model. The results of this study provide a rationale for its beneficial effect seen in the therapy of peptic ulcer disease.