Background — Visceral fat is a key regulator site for the process of inflammation, and atherosclerotic lesions are essentially an inflammatory response. Methods and Results — Fifty-six healthy premenopausal obese women (age range 25 to 44 years, body mass index 37.2±2.2, waist to hip ratio range 0.78 to 0.92) and 40 age-matched normal weight women were studied. Compared with nonobese women, obese women had increased basal concentrations of tumor necrosis factor-α (TNF-α, P <0.01), interleukin-6 (IL-6, P <0.01), P-selectin ( P <0.01), intercellular adhesion molecule-1 (ICAM-1, P <0.02), and vascular adhesion molecule-1 (VCAM-1, P <0.05). Vascular responses to l -arginine (3 g IV), the natural precursor of nitric oxide, were impaired in obese women: reductions in mean blood pressure ( P <0.02), platelet aggregation to adenosine diphosphate ( P <0.05), and blood viscosity ( P <0.05) were significantly lower as compared with those in the nonobese group. Concentrations of TNF-α and IL-6 were related ( P <0.01) to visceral obesity, as well as to adhesin levels and responses to l -arginine. After 1 year of a multidisciplinary program of weight reduction (diet, exercise, behavioral counseling), all obese women lost at least 10% of their original weight (9.8±1.5 kg, range 7.5 to 13 kg). Compared with baseline, sustained weight loss was associated with reduction of cytokine ( P <0.01) and adhesin ( P <0.02) concentrations and with improvement of vascular responses to l -arginine. Conclusion — In obese women, endothelial activation correlates with visceral body fat, possibly through inappropriate secretion of cytokines. Weight loss represents a safe method for downregulating the inflammatory state and ameliorating endothelial dysfunction in obese women.