Intercellular adhesion molecule-1 (ICAM-1) is 1 of the possible factors linking obesity and diabetes with cardiovascular disease, however, the mechanism of the increase in ICAM-1 concentration in obesity remains unclear. Therefore, the aim of the present study was to assess plasma soluble ICAM-1 (sICAM-1) levels in obese subjects with normal glucose tolerance and to evaluate whether those levels may be related to insulin resistance and tumor necrosis factor-alpha (TNFalpha) system activity. The study was performed in 8 lean and 15 obese subjects. Anthropometric and biochemical parameters were measured, and insulin sensitivity was evaluated using the euglycemic hyperinsulinemic clamp technique (insulin infusion, 50 mU x kg(-1) x h(-1)). Obese subjects were markedly more hyperinsulinemic and insulin resistant and had higher plasma soluble TNF receptor 2 (sTNFR2) and sICAM-1 levels. sICAM-1 was related positively to body mass index (BMI), waist-to-hip ratio (WHR), percent of body fat, glycated hemoglobin (HbA(1c)), plasma insulin and triglycerides (TG), TNFalpha, and sTNFR2 and negatively to insulin sensitivity. Multiple regression analysis showed that only sTNFR2 and insulin sensitivity were independent predictors of sICAM-1 concentrations and were responsible for 66% of sICAM-1 variability. We conclude that an increase in plasma sICAM-1 concentration in obesity is related to TNFalpha system activation and insulin resistance.