The relationship among plasma cholecystokinin (CCK), pancreatic growth, and food intake was studied in rats over a 2-wk period of adaptation from a very low-protein to a very high-protein diet. Rats adapted to a control diet (5% casein) were killed at 0900 (without fasting) at 0 h, 12 h, 24 h, 48 h, 7 days, or 14 days after transfer to a high-protein diet (75% casein). CCK was measured by bioassay using isolated pancreatic acini. Plasma CCK in high protein-fed rats was increased approximately threefold in the first 24 h, but returned to control (approximately 2.5 pM) values by day 7. Pancreatic weight, DNA, protein, and chymotrypsin(ogen) significantly increased to maximal values by day 7 in high protein-fed rats. Food intake in high protein-fed rats was inhibited by 47% after 24 h but returned to control values by day 7. The results indicate that high-protein diets initially increase CCK release and increase pancreatic protease secretory capacity and that, when pancreatic protease secretion is sufficient to match protein digestive requirements, the stimulus for CCK secretion is reduced and plasma CCK returns to normal. The pronounced but transient inhibition of food intake in high protein-fed rats is consistent with a role for CCK in regulation of food intake.