Angiogenesis inhibitors have remarkably improved the outcome of patients with several types of cancer. Hypertension is the most reported side effect of angiogenesis inhibitors interfering with vascular endothelial growth factor signaling. In this study, we test the hypothesis that circulating vascular endothelial growth factor at physiological concentrations is essential to preserve normal endothelial control of vasomotor tone. In 7 healthy male volunteers, infusion of bevacizumab (monoclonal vascular endothelial growth factor antibody) into the brachial artery for 15 minutes (144 μg/dL forearm volume per minute) did not affect forearm vasodilator tone as measured with venous occlusion strain gauge plethysmography. In a separate group of 12 male volunteers, a similar bevacizumab infusion reduced the vasodilator response to 2 dosages of acetylcholine from (mean±SE) 440±157% and 926±252% to 169±40% and 612±154% ( P <0.05). Finally, in a third group of 12 volunteers, bevacizumab did not alter the percentage increase in forearm blood flow during infusion of sodium nitroprusside at dosages equipotent to acetylcholine. Bevacizumab acutely and specifically reduced endothelium-mediated vasodilation at local concentrations that resemble plasma concentrations after systemic exposure to bevacizumab. This observation suggests a physiological role for vascular endothelial growth factor in maintaining normal endothelial control of vasomotor tone. The role of the endothelium in the mechanism of bevacizumab-induced hypertension deserves further exploration.