It is known that cholecystokinin (CCK) stimulates islet hormone secretion under a variety of experimental conditions. Since CCK occurs in several different molecular forms, with 58, 39, 33, 12, 8, or 4 amino acid residues, the question has evolved as to which is the shortest active form of CCK. We therefore investigated the influences of the C-terminal octapeptide of CCK, CCK-8 (sulfated form) and of the C-terminal tetrapeptide, CCK-4, on the secretion of insulin, glucagon, and somatostatin from the pig pancreas in vivo by infusing each of the two peptides into the superior pancreatic artery. We found that islet hormone secretion increased promptly upon infusion of both CCK-8 and CCK-4. Thus, the secretion of insulin was stimulated from 51 ± 12 to 295 ± 70 μU/min during the first 2 min after injection of CCK-8 and from 40 ± 12 to 240 ± 78 μU/min after injection of CCK-4. Similarly, the secretion of glucagon was stimulated from 240 ± 45 to 357 ± 38 μg/min after CCK-8 and from 282 ± 44 to 335 ± 43 μg/min after CCK-4, and somatostatin secretion was stimulated from 112 ± 7 to 226 ± 12 μg/min by CCK-8 and from 105 ± 11 to 246 ± 16 pg/min by CCK-4. With regard to the efficiency to stimulate the secretion of these three islet hormones, CCK-8 and CCK-4 were equipotent. We conclude that in pigs, CCK-8 and CCK-4 both stimulate the secretion of insulin, glucagon, and somatostatin from the pancreas in vivo. Hence, the active site in the CCK molecule to stimulate islet hormone secretion in pigs seems to reside in the C-terminal tetrapeptide residue.