OBJECTIVE Acid and fat in the duodenum inhibit gastric acid secretion and increase plasma secretin. The role of prostaglandins and secretin in the inhibition of gastric acid secretion by duodenal infusion of hydrochloric acid and fat in healthy human volunteers was studied. METHODS Gastric acid secretion was submaximally stimulated with intravenous pentagastrin followed by duodenal infusion of 0.1N hydrochloric acid, oleic acid, or intravenous secretin. To inhibit endogenous prostaglandins, the protocol was then repeated after indomethacin treatment. RESULTS Duodenal fat infusion inhibited acid secretion 80% +/- 5% and was unaffected by indomethacin treatment. Intraduodenal acidification inhibited acid secretion by 43% +/- 8% and was reduced by indomethacin treatment to 15% +/- 4% (P < 0.01). Similarly, intravenous secretin inhibited acid secretion by 34% +/- 3%, which was decreased to 13% +/- 6% by indomethacin treatment (P < 0.01). The increase in plasma secretin levels after intraduodenal hydrochloric acid treatment was significantly greater than that observed with intravenous secretin or introduodenal oleic acid treatment; all were within the physiological range. Acid in the duodenum releases secretin, which inhibits gastric acid secretion at least in part via prostaglandins. In contrast, fat in the duodenum strongly inhibits gastric acid secretion via a nonprostaglandin pathway. CONCLUSIONS Secretin is the predominant mediator for the inhibition of human gastric acid secretion induced by the presence of acid, but not fat, in the duodenum.