A 51-yr-old male patient with Cushing's syndrome due to huge nodular adrenocortical hyperplasia is described. Urinary 17-OHCS was not suppressed by a high dose of (8 mg) dexamethasone and showed rather a tendency to paradoxical response. There was no response to metyrapone. Plasma cortisol showed a hyperresponse to insulin-induced hypoglycemia and a rapid response to corticotropin releasing hormone-lysine vasopressin (CRH-LVP) administration without an obvious ACTH response. Plasma cortisol responded to synthetic ACTH. Urinary 17-OHCS did not show parallel changes with plasma cortisol. These results and computerized tomography data suggested huge multiple nodular adrenocortical hyperplasia, which was confirmed later by surgery. The left and right adrenal glands weighed 105 and 45 g, respectively. Hyper-reaction of the adrenal gland to a small change in plasma ACTH or "unknown factors" may cause not only the discrepancy between cortisol and ACTH response but also the development of autonomous nodules in the adrenal gland.