The failure of standard oral pancreatic enzyme replacement therapy to correct malabsorption in patients with advanced pancreatic insufficiency is likely due to acid-peptic inactivation of ingested enzymes. Theoretically, the use of cimetidine, an H2-receptor antagonist, in conjunction with oral enzymes, would permit greater transgastric passage of ingested enzymes with resulting improvement in intraluminal lipolysis. To test this hypothesis, we studied the effects of orally administered cimetidine in two groups of patients by utilizing a previously validated double-marker perfusion technique. Cimetidine, in varying doses, had no effect on postprandial exocrine pancreatic function in 16 duodenal ulcer patients without pancreatic disease. In six patients with pancreatic insufficiency, cimetidine produced a pronounced decrease in the output of gastric acid and secretory volume, resulting in reduction of postprandial acidity and intragastric volume. These actions of cimetidine should retard or prevent inactivation of ingested enzymes and also increase their intragastric concentration, with resulting enhancement of luminal duodenal enzyme activity. Supplemental cimetidine may thus be useful in the medical management of patients who fail to respond to routine pancreatic extract therapy alone.