The effect of central administration of ondansetron, a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist on gastric secretion and gastric cytoprotection was evaluated using four different models of gastric ulcers and cysteamine induced duodenal ulcer. Ondansetron was administered at two different doses of 20 μg/kg, intracerebroventricular (i.c.v.) and 40 μg/kg, i.c.v. Both doses of ondansetron showed significant increase in healing of acetic acid induced gastric ulcers and reduced the formation of ethanol-induced and pylorus ligation-induced gastric ulcers and cysteamine-induced duodenal ulcer. High dose of ondansetron (40 μg/kg, i.c.v.) was more effective compared with the low dose (20 μg/kg, i.c.v.). However, both doses of ondansetron did not influence the development of cold restraint stress induced gastric ulcers. It was concluded that blocking of 5-HT3 receptors in brain decreases gastric acid secretion and increases gastric mucus secretion.