Serum human pancreatic polypeptide (hPP) responses to adrenergic modulation were measured in 24 normal subjects. Epinephrine (6 μg/min) was infused to stimulate adrenergic alpha- and beta-receptors. Beta-receptor stimulation was achieved by infusing epinephrine and selectively blocking alphareceptors with phentolamine, and alpha-receptor stimulation was achieved by infusing epinephrine and blocking beta-receptors with propranolol. Combined alpha- and beta-receptor stimulation caused a small but insignificant rise in hPP concentration. Phentolamine alone caused a twofold rise in hPP concentration, which was abolished by simultaneous atropine infusion. Propranolol alone had no effect. Adrenergic beta-receptor stimulation with epinephrine plus phentolamine caused a sevenfold rise from 45 ± 10 to 351 ± 60 pM (P < 0.05), whereas adrenergic alpha-receptor stimulation caused a significant fall from 100 ± 25 pM (the rise in hPP concentration induced by epinephrine) to 44 ± 7.8 pM. The changes in hPP concentration did not correlate with changes in serum insulin, glucose, or free fatty acid (FFA) concentrations. The pattern of the response was quite different from insulin, which reached a peak within 1 min of phentolamine administration, whereas hPP levels rose slowly to a peak at 45 min. The rise induced by adrenergic beta-receptor stimulation with epinephrine plus phentolamine was equivalent to the rise from 40 ± 11 to 280 ± 48 pM caused by an insulin-induced fall in serum glucose of about 50% and that induced by isoproterenol infusion, which caused a fourfold rise from 69 ± 3 to 271 ± 84 pM. These data suggest that the adrenergic system may be important in the regulation of hPP release.