To clarify the role of duodenal mucosal blood flow in the genesis of duodenal mucosal lesions, a single dose of serotonin, 20 mg/kg, was administered subcutaneously to rats. Serotonin significantly decreased both the duodenal mucosal blood flow and the output of gastric acid and pepsin. However, mild duodenal erosions were observed in only 2 of the 9 rats receiving that agent. The repeated intragastric administration of 1 ml of 0.1 N HCl hourly for 6 h failed to induce duodenal mucosal lesions. On the other hand, the administration of both serotonin and repeated doses of HCl produced marked duodenal mucosal lesions in all rats. It is concluded, therefore, that one of the factors responsible for the genesis of duodenal mucosal lesions is a decrease of duodenal mucosal blood flow combined with an acid load against the duodenal mucosa.