The role of endothelin (ET)-B (ETB) receptors in mediating vasoconstriction in humans is unclear. As yet, in vitro data have been contradictory, and there have been no in vivo studies in resistance vessels. We investigated the function of ETB receptors in vivo in human forearm resistance vessels using ET-1 as a nonselective agonist at ETA and ETB receptors and ET-3 and sarafotoxin S6c as ETB receptor agonists. Brachial artery infusion of ET-1 and ET-3 caused slow-onset, dose-dependent forearm vasoconstriction. Although ET-3 caused significantly less forearm vasoconstriction than ET-1 at low doses, vasoconstriction to the two isopeptides was similar at the highest dose (60 pmol/min). ET-3 caused initial transient forearm vasodilatation at this dose, whereas ET-1 showed only a nonsignificant trend toward causing early vasodilatation. Intra-arterial sarafotoxin S6c caused a progressive reduction in forearm blood flow, although less than that to ET-1. Therefore, ETB receptor agonists contract human resistance vessels in vivo. The effects of ET-3 and sarafotoxin S6c, compared with ET-1, suggest that both ETA and ETB receptors mediate vasoconstriction. Antagonists at both ETA and ETB receptors, or inhibitors of the generation of ET-1, may be necessary to completely prevent vasoconstriction to endogenously generated ET-1.