The weight gain and visceral obesity associated with Cushing's syndrome (CS) has been linked to elevated plasma leptin levels, although the mechanism behind a central leptin resistance in these patients is unknown. Several studies describe interactions among the hypothalamic-pituitary-adrenal axis, leptin, and the IL-1 system. To investigate these interactions, we have evaluated changes in regional fat distribution, by DEXA, and the role of circulating cortisol, leptin, IL-1beta, and IL-1 receptor antagonist (IL-1Ra), in relation to these changes, in 27 (19 DEXA; 27 serum measurements) patients with CS, before and after surgical treatment (mean follow-up, 31 months; range, 5-80), and compared them with measurements of age-, sex-, and body mass index-matched healthy controls (also obtained longitudinally). We found that surgical treatment caused a decrease in all fat parameters, without changing lean body mass, and these changes were significantly larger than the so-called natural changes occurring in control subjects. These changes in CS patients were paralleled by decreases in cortisol, leptin, and IL-1Ra, whereas IL-1beta increased. Stepwise linear regression showed that serum IL-1Ra was strongly associated with regional fat distribution, and especially truncal fat mass, both at baseline and during treatment. In conclusion, the present study shows that treatment significantly changes body composition in CS patients by decreasing fat mass, especially in the truncal region, without major effects on lean body mass. We also show that circulating IL-1Ra is strongly associated with these changes, signifying a relationship among the hypothalamic-pituitary-adrenal axis, IL-1 system, and regional fat distribution in these patients.