Rats were given subcutaneous injections of secretin (12.5 microgram kg-1) plus caerulein (0.5 microgram kg-1) in a depot carrier or depot carrier alone every 8 hr for 10 days. Basal pancreatic secretion and responses to secretin and cholecystokinin were then studied while the rats were under urethane anesthesia. In the treated animals, basal secretion of fluid was more than six times greater, basal bicarbonate output more than three times greater, and and basal protein output more than two times greater than in the control rats (P less than 0.01 for each). After subtracting basal values and normalizing for body weight, the treated group means were statistically significantly greater than those of the control for: maximal bicarbonate output (1.81 times control) to secretin; and maximal outputs to cholecystokinin of volume (2.46 times control), bicarbonate (2.69 times control), and protein (2.28 times control). The mean pancreatic weight per kilogram of body weight in the treated group was 1.65 times (P less than 0.01) that of the control group. When normalized for pancreatic weight (basal values subtracted), the increse in maximal protein output (1.37 times control) to cholecystokinin was still statistically significant (P less than 0.05). We conclude that chronic treatment with secretin plus caerulein exerts a trophic effect on the pancreas associated with increased maximal protein output to cholecystokinin and increased maximal bicarbonate output to secretin.