The effects of luminal bile salts on plasma levels of cholecystokinin (CCK) and growth of the pancreas in mice were studied. Nonfasting levels of plasma CCK in control mice were 8.1 +/- 1.5 pM. Feeding mice a 0.5% (wt/wt) sodium taurocholate-supplemented diet for 1 wk significantly lowered nonfasting levels of plasma CCK to 4.1 +/- 0.5 pM and decreased the total contents of pancreatic DNA by 22%, RNA by 25%, and protein by 24%. All of the inhibitory effects of taurocholate on pancreatic growth were completely reversed by the simultaneous administration of CCK-8 (3 micrograms/kg, 3 times daily). In contrast, intraluminal neutralization of endogenous bile salts by feeding a 4% (wt/wt) cholestyramine-supplemented diet for 1 wk significantly elevated nonfasting levels of plasma CCK to 14.7 +/- 1.5 pM and increased the total contents of pancreatic DNA by 34%, RNA by 40%, and protein by 35%. All of the stimulatory actions of cholestyramine on pancreatic growth were completely abolished by the administration of the highly potent and specific CCK-receptor antagonist L364,718 (1 mg/kg, twice daily). These findings, therefore, indicate that bile salts appear to play a physiological role in pancreatic growth by regulation of plasma levels of CCK.