Introduction Leptin has emerged as an important peptide in metabolic regulation, with obese patients often being resistant to leptins effects. Recently studies have suggested that leptin may also have vasoactive effects. We explored this possibility in human patients undergoing coronary artery bypass surgery. Methods and Results The vasoactive effect of leptin was assessed ex-vivo in saphenous vein (SV) rings obtained at time of CABG. 131 patients undergoing CABG were recruited (age 66 ± 0.9, (mean ± SEM) 90% male).These patients had body mass index 26.8 ± 0.4 kg/m2, waist circumference 99.2 ± 1.0 cm, systolic blood pressure 138.6 ± 2.0 mmHg, diastolic blood pressure 74.4 ± 1.2 mmHg, fasting glucose 6.5 ± 0.2mmol/L, LDL cholesterol 1.8 ± 0.06mmol/L, HDL cholesterol 1.0 ± 0.2mmol/L. Vascular reactivity to leptin (10-13-10-7M) in all patients (n=131) was assessed in preconstricted SV rings. Mean maximal relaxation to leptin was 24.5 ± 1.6%, all rings relaxed fully to sodium nitroprusside. To explore the mechanism of leptins vasorelaxant effect we performed studies (n=8) in the presence of the non-specific nitric oxide synthase inhibitor L-NMMA (10-4M) this had no effect on leptin induced vasorelaxation (17.4 ± 3.4 versus 17.8± 3.3% P=0.9), endothelial denudation had no effect on leptin induced vasorelaxation (17.4 ± 4.4 versus 22.5 ± 3% P=0.4). Leptins central effect is thought to be mediated by acting on potassium channels, to explore the possibility that its actions on the vasculature are mediated in a similar fashion we inhibited hyperpolarisation (KCl 30mmol/L), this completely blocked the effect of leptin (12.6 ±5.6 versus 0.08 ± 4.1%, P<0.001). To assess the relationship between total body fat and leptins vascular effect we went on to correlate body mass index (range 16.5 – 39.1Kg/m2) with maximal leptin induced vasodilatation (range 0 – 102.9%) in the whole population. However there was no correlation between these variables (r=0.05, P=0.55). Conclusions These data demonstrate for the first time that leptin is a vasoactive peptide in human veins, moreover leptin does not act in an NO or endothelial dependent manner. These data also show that leptins vasoactive effects are preserved in obese patients supporting tissue specificity of leptin resistance in humans.