It has been suggested that a low grade inflammatory state could predispose for developing insulin resistance and contribute to the development of obesity and type 2 diabetes. Corticosteroid-binding globulin (CBG), the main plasma protein transport for cortisol, has been shown to be negatively regulated by insulin and IL-6, at least in vitro, suggesting that insulin resistance and inflammation may both contribute to decreasing CBG levels. In the present study we measured CBG concentrations in a human healthy population and investigated the relationships of CBG with anthropometric and biochemical markers for inflammation and/or insulin resistance. The data showed that the mean serum CBG level was significantly lower in males (n = 151) than in females (n = 113; 32.5 +/- 9.1 vs. 39.2 +/- 13.9 mg/liter; P < 0.0001). In both sexes serum CBG levels were correlated negatively with age (r = -0.12; P = 0.04), body mass index (r = -0.31; P < 0.0001), waist to hip ratio (WHR; r = -0.39; P < 0.0001), systolic (r = -0.15; P < 0.01) and diastolic (r = -0.15; P = 0.01) blood pressures, and HOMA, an index of insulin resistance (r = -0.12; P = 0.04). In addition, the CBG concentration was negatively associated with serum IL-6 concentrations (r = -0.23; P = 0.017) and with the soluble fraction of TNFalpha receptors, soluble TNF receptor 1 (sTNFR1; r = -0.35; P < 0.0001), and sTNFR2 (r = -0.56; P < 0.0001) in women. A stepwise regression analysis using CBG as an independent variable showed that sex (P < 0.00001), body mass index (P = 0.0002), and HOMA (P = 0.0005), but not systolic blood pressure, diastolic blood pressure, IL-6, sTNFR1, or sTNFR2, constituted significant independent factors that explained 21% of the CBG variance (14%, 2%, and 5%, respectively). In a subsample of 120 men and 68 women, fasting serum free cortisol (calculated as the ratio fasting cortisol/CBG) was significantly associated with WHR (r = 0.24; P = 0.001), systolic (r = 0.18; P = 0.01) and diastolic (r = 0.19; P = 0.007) blood pressures, and HOMA value (r = 0.20; P = 0.005), but not with BMI or age. BMI (P < 0.0001), free cortisol (P = 0.003), and CBG (P = 0.009), but not WHR and age, contributed to 20%, 6%, and 8%, respectively, of HOMA variance in women in a multiple regression analysis. In this model only BMI (P < 0.0001) independently contributed to HOMA variance in men. These findings support the hypothesis that the CBG level is an interesting indicator for both insulin resistance and low grade inflammation. Whether the decrease in CBG levels is genetic by nature or directly associated to increased insulin and/or IL-6 merits further investigation. Nevertheless, because CBG has been shown to be expressed by the adipose tissue, decreased CBG could create locally increased cortisol disposal, with no change in circulating cortisol, and facilitate fat accumulation, insulin resistance, and type 2 diabetes.