Cyproheptadine, a nonselective 5-hydroxytryptamine receptor blocking agent, reduces ACTH and beta-endorphin secretion from the ACTH-producing tumors. A 35-year-old female suffering from Cushing's disease due to microadenoma of the pituitary gland has been followed since the age of 15. Subtotal adrenalectomy followed by total adrenalectomy, pituitary irradiation, and transsphenoidal hypophysectomy, combined with second radiotherapy of the pituitary, were unsuccessful in achieving remission of the disease. Remission was achieved with cyproheptadine up to a dosage of 24 mg/day. Every attempt to discontinue cyproheptadine treatment was accompanied by recurrence of the disease. This is the first case of Cushing's disease in which cyproheptadine treatment has been the only efficacious therapy for a period of 11 yr. Cyproheptadine may be an alternative long-term therapy for Cushing's disease when other methods of treatment fail.