Duodenal ulcers can be produced in rats within 24 h by a single subcutaneous administration of cysteamine. To determine the role of gastric acid secretion in the pathogenesis of these ulcers, secretory and pathoanatomic studies were performed in chronic fistula rats ater an ulcerogenic dose of cysteamine. A prolonged increase of acid secretion was seen after cysteamine, reaching fourfold the basal level after 5 h. The acid response lasted for 10 to 11 h. After vagotomy cysteamine-induced acid secretion was markedly reduced. Ulcer formation was prevented by vagotomy and by drainage of the gastric juice before it entered the duodenum. When a gastric acid output equivalent to that produced by the ulcerogenic dose of cysteamine was induced by repeated injections of pentagastrin, no mucosal changes were seen in the duodenum. These results indicate that, although some acid in the duodenum is required for ulcer formation, the hypersecretion of acid induced by cysteamine is not the only factor responsible for the development of duodenal ulcer.