The pathophysiology of macronodular adrenocortical hyperplasia (MNH) associated with Cushing's diseases remains debatable. Some authors have claimed that MNH represents an autonomous condition that has to be treated by surgical adrenalectomy while others advocate the use of pituitary surgery. We have compared the biochemical features, before and after pituitary surgery, between 7 cases of MHN and 22 cases of diffuse hyperplasia (DH) associated with Cushing's disease. In addition, the diameter of the adrenal nodules after surgery was evaluated in 6 cases. The mean ACTH level in MNH and DH subjects was similar. Dexamethasone suppressibility and the stimulatory effect of metyrapone on ACTH secretion were less in MNH than in DH subjects, suggesting a greater degree of adrenal autonomy in the former. The cortisol responses to metyrapone and CRF tests suggested an increased responsiveness of the adrenals to endogenous ACTH in the MNH group. Only one MNH patient had biochemical features suggesting a primary adrenal disease. The use of a sensitive ACTH assay and the results of inferior petrosal sinus sampling identified the ACTH-dependency of the disease. A short to medium term remission of the disease was obtained in all cases of MNH and in 87% of cases of DH after surgery. The diameter of the adrenal nodules significantly decreased in only 43% of cases. Our results suggest that the adrenal autonomy in MNH is incomplete and that, despite the persistence of the adrenocortical nodules, the disease can be cured with pituitary microsurgery in most cases.