Pentagastrin (1.5 mg/kg), 20% pure natural cholecystokinin (CCK, 37.5 Ivy dog U/kg) or secretin (25 microgram/kg) was given in a depot carrier subcutaneously to rats 3 times daily for 15 days. The dose of CCK and secretin was submaximal for pancreatic secretion, whereas the dose of pentagastrin was supramaximal for gastric acid secretion. The pancreatic wet weight increased by 12% (P less than 0.01) in the rats treated with pentagastrin, 57% (P less than 0.001) in those treated with CCK, and 9% (P less than 0.01) in those treated with secretin. In CCK-treated rats, the maximal protein and bicarbonate outputs in response to cholecystokinin increased proportionately to the increase in pancreatic weight, but maximal bicarbonate and protein outputs in response to secretin were unaltered. The secretin-treated rats showed a lowered basal secretion of bicarbonate and a lowered sensitivity to secretin stimulation, but the maximal bicarbonate and protein outputs to secretin and CCK were unchanged. Treatment with pentagastrin produced no significant changes in pancreatic responses to secretin or CCK. We conclude that 1) the increase in pancreatic weight produced by repeated injections of cholecystokinin was accompanied by proportional increase in functional capacity as reflected by the increased maximal bicarbonate and protein outputs in response to cholecystokinin, and 2) repeated administration of secretin decreased the sensitivity of the pancreas to secretin without altering maximal bicarbonate response.