OBJECTIVE PPAR-gamma agonists are able to inhibit pituitary tumour development and tumoral hormonal secretion in rodents both in vitro and in vivo. Their use for treatment of Cushing Disease (CD) has been suggested but the clinical experience with the two PPAR-gamma agonists commercially available (rosiglitazone and pioglitazone) was not impressive. Short-time treatment has been proposed to be the cause of unsuccessful results on CD in humans. We report here the effect on early-morning plasma cortisol levels of a long-time treatment with rosiglitazone at the highest approved dose. METHODS Because PPAR-gamma receptors are located in normal corticotroph cells we tested in a placebo-controlled study the influence of rosiglitazone on cortisol secretion. The study enrolled 30 newly diagnosed type 2 patients which were assigned to receive either rosiglitazone (8 mg/day) or placebo. Plasma morning cortisol (8.00 a.m.) was measured at the baseline and at the end of the study. RESULTS Rosiglitazone vs placebo did not modify the early morning plasma levels of cortisol (13 microg/dl [3-21] vs 11 microg/dl [7-23] [median and range]) after 26 weeks of treatment. CONCLUSIONS The discrepancy between in vitro and animal data on one side and clinical data on the other side warrant further investigations into the mechanisms of action of PPAR-gamma agonists on ACTH secretion before other clinical studies will be conducted.