Obese patients have impaired vasodilator reactivity and increased endothelin (ET)-1-mediated vasoconstriction, two abnormalities contributing to vascular dysfunction. Obestatin, a product of the ghrelin gene, in addition to favorable effects on glucose and lipid metabolism, has shown nitric oxide (NO)-dependent vasodilator properties in experimental models. Given these premises, we compared the effects of exogenous obestatin on forearm flow in lean and obese subjects and assessed its influence on ET-1-dependent vasoconstrictor tone in obesity. In both lean and obese participants, infusion of escalating doses of obestatin resulted in a progressive increase in blood flow from baseline (both P<0.001); this vasodilation was predominantly mediated by enhanced NO activity, because L-NMMA markedly blunted the flow response to obestatin in both groups (both P<0.05 vs. saline). In obese subjects, antagonism of ETA receptors by BQ-123 increased forearm flow during saline (P<0.001), but did not induce additional vasodilation (P>0.05) during obestatin. Circulating obestatin levels were not different between lean and obese participants (P=0.41). Our findings indicate that obestatin causes NO-dependent vasodilation in the human circulation. This effect is preserved in obesity, where it is accompanied by reduced ET-1-mediated vasoconstriction. These latter observations make obestatin a promising target for vascular prevention in obesity and diabetes.