Nerve fibers containing neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), substance P (SP), and calcitonin gene-related peptide (CGRP) were seen in the adventitia or at the adventitia-media border of the human temporal artery. Pharmacological experiments on isolated temporal artery segments revealed that NPY potentiated the vasoconstrictor responses to noradrenaline, but had no vasoconstrictor ability or only a small vasoconstrictor ability per se. VIP, peptide histidine methionine 27 (PHM-27), SP, neurokinin A (NKA), and CGRP potently relaxed vessels precontracted by prostaglandin F2 alpha, the relative potency being CGRP greater than SP greater than NKA = VIP = PHM-27. The amount of relaxation varied between 67 and 91% of the prostaglandin F2 alpha-induced contraction. The peptide effects were not antagonized by classic adrenergic or cholinergic blockers, suggesting interactions via separate receptor sites.