Serum trypsin-like immunoreactivity (TLI) was studied after administration of secretin (GIH, 75 CU i.v.) in 10 alcoholics and in 3 patients with type IV hyperlipoproteinemia. A significant increase of TLI was observed after secretin administration and persisted throughout the test. In order to assess the possibility of an acid-sensitive effect, the test was repeated on a different day, one hour after the administration of cimetidine (400 mg. p.o.). Cimetidine did not affect serum TLI for one hour, but did reduce significantly the response of serum TLI to injection of secretin (p < 0.01). Some studies were performed, which failed to show any effect of cimetidine on pancreatic exocrine function. However, they were based on the measurement of pancreatic secretion into the duodenum, which required aspiration of gastric secretion from the stomach before entering the duodenum. Therefore, the reduction of TLI response to injection of secretin may be tentatively attributed to the inhibition of gastric acid secretion and delivery to the duodenum caused by cimetidine. If an endogenous acid-sensitive mechanism is involved, it is unlikely to be mediated by secretin.