A patient with Cushing's disease was treated with cyproheptadine with concomitant remission of the disease for 60 months. Despite clinical improvement and achievement of normal levels of cortisol excretions, her menstruation-related cyclic surge of cortisol secretion was supranormal. The mode of action of cyproheptadine was studied by the administration of metyrapone. Long-term administration of cyproheptadine appeared to normalize excessive adrenocorticotropic hormone (ACTH) production by reducing the frequency and the peak levels of episodic secretion of ACTH.