The role of cholecystokinin (CCK) in induction and maintenance of pancreatic growth stimulated by a high-protein diet was investigated. Rats adapted to 5% casein diet were switched to 70% casein for 21 days. MK-329, a CCK receptor antagonist, was administered at 2.5 mg.kg-1.day-1 ip, beginning on day zero (day zero treatment) or day 7 (midcourse treatment) of feeding 70% casein and thereafter. Another group was returned to 5% casein after 7 days of feeding 70% casein. Feeding 70% casein significantly stimulated increases of 32, 87, 74, 216, and 1,450% in pancreatic DNA, RNA, wet weight, protein content, and chymotrypsin content, respectively. Midcourse treatment with MK-329 was more effective than day zero treatment, and it completely reversed increases in pancreatic weight and RNA content, partially reversed increases in protein and chymotrypsin content, and had no effect on DNA content. Return to 5% casein rapidly reversed increases in pancreatic parameters, except for DNA. The results indicate that CCK is essential for induction and maintenance of dietary protein-stimulated pancreatic hypertrophy.