The effect of perfusion of the jejunum with acid on the secretion of bicarbonate, trypsin, and bile into the duodenum has been studied in 10 patients with duodenal ulcer and 8 control subjects and compared with the responses to intravenous infusion of secretin and cholecystokinin-pancreozymin (CCK). Both the secretion of bicarbonate and of trypsin into the duodenum were inversely related to the amount of acid dissipated during jejunal transit, so that if all the acid disappeared during transit of a 30-cm segment of jejunum, the pancreas did not secrete. In both groups of subjects, jejunal acidification elicited a relatively greater secretion of bicarbonate than secretion of trypsin or bile into the duodenum, compared with the response to the exogenous hormones. Jejunal acidification also inhibited the secretion of trypsin in response to concurrently administered exogenous hormones by the control subjects but not in patients with duodenal ulcer. We conclude taht the pancreatic response to acid in the human duodenum depends on exposure of the jejunal mucosa to the amounts of acid which are greater than (quite high, but variable) threshold in all subjects. Under the conditions of this study, patients with duodenal ulcer differed from control in lacking an acid-released jejunal inhibitor of the secretion of trypsin by the pancreas.