Release of pancreatic polypeptide (PP) after a meal is biphasic, with an early transient peak believed to be under cholinergic control, and a secondary, prolonged intestinal phase thought to be mediated by hormones. Endogenous release of PP was stimulated by intraduodenal oleate (6.8 mmol/hr) or by intravenous administration of pure cholecystokinin-33 (CCK-33, 0.1 micrograms/kg/hr) in five dogs. Radioimmunoassay measurements of plasma concentrations of PP and CCK-33 were compared by linear regression analysis before and after vagotomy. Correlations between plasma concentrations of PP and CCK-33 before vagotomy (r = 0.83 [oleate], r = 0.97 [IV-CCK-33]) and after vagotomy (r = 0.92 [oleate], r = 0.92 [IV-CCK-33]) were highly significant. Changes in plasma concentrations of PP relative to a particular increment in plasma CCK-33 (before vagotomy) were similar, whether stimulated by oleate or by exogenous CCK-33. After vagotomy, less PP was released relative to a change in plasma CCK-33 (stimulated by oleate or by exogenous CCK-33), but the PP response relative to a change in plasma CCK-33 induced by the two stimuli remained remarkably similar. These results provide evidence that the intestinal phase of physiologic release of PP is mediated to a large extent through release of CCK.