Anabolic corticosteroids have been reported to enhance glucose effectiveness (SG). In experimental models of long-term cortisol infusion in diabetic dogs, the maintenance of normal SG during chronic hypercortisolemia prevented a significant deterioration of glucose tolerance. We hypothesized that in analogy with exogenous corticosteroids, endogenous cortisol might influence SG. We aimed to study the influence of serum cortisol on SG prior to a frequently sampled intravenous glucose tolerance test (FSIVGTT) in 18 otherwise healthy men. The serum cortisol level or free cortisol index (ratio of cortisol to cortisol-binding globulin [CBG]) were not associated with the body mass index (BMI), waist to hip ratio (WHR), fasting insulin, or insulin sensitivity ([SI] all r < .20, P = NS). Conversely, SG correlated with serum cortisol levels measured prior to the FSIVGTT (r = .60, P = .008) and with the free cortisol index (r = .48, P = .03). The association was stronger in lean subjects (BMI < 25 kg/m2, r = .90, P = .002, n = 8). Men with a pre-FSIVGTT serum cortisol level above the median (431 nmol/L) were similar by age, BMI, WHR, and SI to the subjects with cortisol levels below the median, but the latter presented a significantly decreased SG (0.0014 +/- 0.006 v 0.022 +/- 0.007 min(-1), P = .03). In multiple linear regression analysis, fasting glucose (P = .02) and serum cortisol (P = .027) independently predicted SG, contributing to 26% of its variance. In summary, our findings suggest that the prevailing cortisol level appears to be associated with SG. The lower cortisol levels usually found in abdominally obese men could contribute to their altered glucose tolerance, perhaps via decreased SG.