Controversy exists whether endogenous cortisol production is associated with visceral obesity and insulin resistance in humans. We therefore quantified cortisol production and clearance rates, abdominal fat depots, insulin sensitivity, and adipocyte gene expression in a cohort of 24 men. To test if found relationships are a consequence rather than a cause of obesity, 8 men from this larger group were studied before and after weight loss. Daily cortisol production rates (CPR), free hormone levels (FC), and metabolic clearance rates (MCR) were measured by stable isotope methodology and 24-hour sampling; intra-abdominal fat (IAF) and subcutaneous fat (SQF) by computed tomography; insulin sensitivity (SI) by frequently-sampled intravenous glucose tolerance test; and adipocyte 11 hydroxysteroid dehydrogenase-1 (11 Beta HSD-1) gene expression by quantitative RT PCR from subcutaneous biopsies. Increased CPR and FC levels correlated with increased IAF, but not SQF, and with decreased SI. Increased 11 Beta HSD-1 gene expression correlated with both IAF and SQF, and with decreased SI. With weight loss, CPR, FC, and MCR did not change compared to baseline; however, with greater loss in body fat than lean mass during weight loss, both CPR and FC increased proportionally to final fat mass and IAF; and 11 Beta HSD-1 decreased compared to baseline. These data support a model in which increased HPA activity in men promotes selective visceral fat accumulation and insulin resistance and may promote weight regain after diet-induced weight loss, whereas 11 Beta HSD-1 gene expression in subcutaneous fat is a consequence rather than cause of adiposity.