The vasodilator effect of the novel peptide pituitary adenylate cyclase activating polypeptide (PACAP) was investigated in humans. Forearm blood flow was measured in six healthy men by venous occlusion plethysmography. Infusion of PACAP into the brachial artery at 0.01, 0.1, 1, 3, and 10 pmol/min produced a dose-related increase in forearm blood flow in the cannulated arm from 2.8 ± 0.6 to 8.6 ± 2.4 ml/100 ml/min at the highest dose (mean ± SEM, p < 0.05). In a subsequent experiment, where the highest dose of PACAP was repeated after a 36 min interval, there was no tachphylaxis of the forearm blood flow response, with the forearm blood flow increasing by 129 ± 9% during the first infusion and 128 ± 31% during the second infusion (N.S.). In further experiments, microvascular blood flow was measured by a laser-Doppler flow probe to compare the effects of intradermally injected PACAP, vasoactive intes- tinal polypeptide (VIP), and calcitonin gene-related peptide (CGRP). When injected into the skin of normal volunteers at 10-l2 to 10-11 mol/site, each peptide caused a rapid flare lasting 2–3 min, which became erythematous after 5 min. At 10“12 mol/site, intradermally injected PACAP and VIP caused a maximum increase in skin blood flow at 15 min of 379 ± 96 and 307 ± 121% (% increase above basal ± SEM), respectively, and these responses were not significantly affected by oral aspirin (600 mg) taken 1.5 h beforehand. The vasodilation induced by PACAP at 10-12 mol/site lasted approximately 6 h, whereas the effect of the same dose of CGRP and VIP lasted less than 2 h. These data suggest that PACAP is a potent and long-lasting vasodilator in humans.