Recent studies have shown that leptin causes vasodilation. However, it is unclear whether leptin causes coronary vasodilation in humans. To determine how leptin affects human coronary arteries and whether endothelium-derived nitric oxide (EDNO) is involved in the coronary arterial response to leptin, we infused leptin (0.3, 3 and 30 ng/kg/min) for 2 min into the left coronary ostium before and after an infusion of nitric oxide synthase inhibitor, N^G-monomethyl-L-arginine (L-NMMA), in 11 men with angiographically normal coronary arteries. The diameter of the epicardial coronary arteries was quantitatively measured, and coronary blood flow (CBF) was calculated by quantitative angiography and Doppler flow velocity measurements. The changes in these parameters in response to leptin are expressed as the % change from the baseline values. Leptin caused coronary dilation (0.3 ng/kg/min: 2.0±0.5%; 3 ng/kg/min: 4.9±0.7%; 30 ng/kg/min: 3.8±0.9%) and increased CBF (13.6±3.3%, 36.8±5.6%, and 39.2±7.4%, respectively). After the infusion of L-NMMA, leptin also caused coronary dilation (2.0±0.4%, 4.5±0.7%, and 4.6±0.8%, respectively) and increased CBF (14.6±2.8%, 39.2±5.7%, 40.3±6.2%, respectively). Leptin-induced coronary vasodilation was not affected by the infusion of L-NMMA. These results suggest that leptin dilates coronary arteries in humans. Furthermore, EDNO may not contribute to leptin-induced coronary dilation. (Hypertens Res 2003; 26: 147-152)