Pancreatic insufficiency was induced in rats by a single injection of 50 microliter oleic acid into the pancreatic duct over a period of 3 min. Exocrine tissue was destroyed within 3-6 days, and after 6 weeks the remaining pancreas equaled 2.7% of the original organ. The rats showed retardation of body weight in spite of normal food intake. After 7 weeks the fecal weight increased by 23%, and the fecal chymotrypsin activity decreased by 90% compared to controls. At this time plasma cholecystokinin (CCK) concentrations were significantly elevated. The amylase content in the remaining pancreas was reduced by 99%, and trypsin content was reduced by 93%. Unstimulated protein discharge from the remnant pancreas in vitro was threefold higher compared to secretion from control tissue. Thus a simple, reproducible model for inducing persistent pancreatic insufficiency was developed. To compensate for the loss of exocrine tissue, the remaining acinar cells adapt by a CCK-mediated increase in protein secretion.