Neuropeptide Y (NPY), substance P (SP), vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), lysyl-bradykinin, somatostatin, Met- and Leu-enkephalin were tested for their smooth muscle activity in isolated human mesenteric arteries and veins. Only NPY regularly contracted both arteries and veins. Alpha-adrenergic and 5-HT2 antagonists did not affect the response. Somatostatin contracted the veins, but not the arteries, in a variable but concentration-dependent way. The other neuropeptides were without contractile effect. CGRP, bradykinin, and SP regularly dilated, in a concentration-dependent way, both arteries and veins precontracted with prostaglandin F2 alpha or uridine triphosphate. CGRP and bradykinin were the most potent dilators. VIP and somatostatin usually caused a moderate dilatation in the arteries, whereas in the veins, somatostatin was without dilatory effect and the VIP-induced dilatation was irregular. In both types of vessels Met-enkephalin seldom gave any significant dilatation, and no response occurred in the presence of Leu-enkephalin or NPY. The SP-antagonist (D-Arg, D-Trp, Leu)-SP (spantide) caused a dextal shift of the concentration-response curves for SP, in the case of the arteries also including a reduced maximum effect.