The effects of long-term administration of cholecystokinin octapeptide (CCK-8) with or without secretin on the pancreas were examined in groups of rats treated with: (1) CCK-8 (1 microgram kg-1); (2) secretin + CCK-8 (1 microgram kg-1 of each); or (3) saline, administered subcutaneously twice daily for 5 out of 7 days for 6 or 12 months. A number of rats from all groups were studied for: (1) pancreatic size and biochemical composition (n = 6 for each group); (2) pancreatic secretion in the anesthetized state (n = 5 for each group); and (3) pancreatic histology (n = 6 for each group) after a 6-month treatment period. The rest of the animals treated for an additional 6-month period (n = 13 for each group) were examined for pancreatic size and histology. CCK-8 increased the weight of the pancreas and its contents of DNA, protein, trypsinogen, chymotrypsinogen, proelastase, secretory trypsin inhibitor and amylase, but not that of lipase when given for 6 months, whereas administration of secretin + CCK-8 doubled the pancreatic content of lipase and increased all trophic parameters (except the amylase content) over those of CCK-8-treated rats. Maximum pancreatic volume and protein outputs in response to CCK-8 were higher in both of the hormone-treated groups than in the control; the sensitivity to the secretory action of CCK-8 was not altered. Pancreatic mass increased in response to either treatment after 12 months as well. Histological examination did not reveal pancreatic neoplasia in either group. The results indicate that long-term administration of CCK-8 or secretin + CCK-8 in rats results in sustained pancreatic hypertrophy and hyperplasia with secretory hyperfunction with no evidence of neoplastic alterations.