Obesity is associated with increased cardiovascular risk. Although short-term weight loss improves vascular endothelial function, longer term outcomes have not been widely investigated. We examined brachial artery endothelium-dependent vasodilation and metabolic parameters in 29 severely obese subjects who lost > or =10% body weight (age 45 +/- 13 years; BMI 48 +/- 9 kg/m(2)) at baseline and after 12 months of dietary and/or surgical intervention. We compared these parameters to 14 obese individuals (age 49 +/- 11 years; BMI 39 +/- 7 kg/m(2)) who failed to lose weight. For the entire group, mean brachial artery flow-mediated dilation (FMD) was impaired at 6.7 +/- 4.1%. Following sustained weight loss, FMD increased significantly from 6.8 +/- 4.2 to 10.0 +/- 4.7%, but remained blunted in patients without weight decline from 6.5 +/- 4.0 to 5.7 +/- 4.1%, P = 0.013 by ANOVA. Endothelium-independent, nitroglycerin-mediated dilation (NMD) was unaltered. BMI fell by 13 +/- 7 kg/m(2) following successful weight intervention and was associated with reduced total and low-density lipoprotein cholesterol, glucose, hemoglobin A(1c), and high-sensitivity C-reactive protein (CRP). Vascular improvement correlated most strongly with glucose levels (r = -0.51, P = 0.002) and was independent of weight change. In this cohort of severely obese subjects, sustained weight loss at 1 year improved vascular function and metabolic parameters. The findings suggest that reversal of endothelial dysfunction and restoration of arterial homeostasis could potentially reduce cardiovascular risk. The results also demonstrate that metabolic changes in association with weight loss are stronger determinants of vascular phenotype than degree of weight reduction.