To determine whether pancreatic polypeptide (PP) is a physiologic inhibitor of pancreatic secretion, we have studied the effects of normal rabbit serum and anti-PP serum on pancreatic secretion during infusion of a physiologic dose of PP or intragastric food instillation in dogs. Infusion of 180 pmol/kg · h of PP, previously incubated with normal rabbit serum, induced increases in plasma PP (220 ± 21 pmol/L) similar to those after the meal (213 ± 51 pmol/L) and was accompanied by significant inhibition of pancreatic flow rate, bicarbonate output, and protein output (p < 0.05) stimulated by secretin and cholecystokinin (n = 6). However, when the effect of exogenous PP was studied after in vivo administration of anti-PP serum or after previous in vitro incubation with anti-PP serum, no inhibition of pancreatic secretion was found, indicating that immunoneutralization of PP blocks the biologic activity of the hormone. Intragastric instillation of 400 ml of liver extract resulted in significant increases in pancreatic flow rate and outputs of protein and bicarbonate (p < 0.01; n = 8), both during administration of normal rabbit serum and anti-PP serum. The postprandial increase in pancreatic secretion during administration of anti-PP serum was not significantly different from that during administration of normal rabbit serum. We, therefore, conclude that PP is not a physiologic inhibitor of postprandial pancreatic secretion.