Twenty adult patients with Cushing's disease treated with long term reserpine administration in combination with a single course of external pituitary irradiation were followed. Eleven patients experienced long term remissions of 15.5 +/- 8.9 (mean +/- SD) yr (55%) after a mean irradiation dose of 53.9 +/- 11.4 Gy and a mean duration of reserpine administration of 24.3 +/- 9.3 months. The long term remission rates of the patients irradiated with 50 Gy or less (n = 9; 45.0 +/- 7.1 Gy) and those with more than 50 Gy (n = 10; 61.3 +/- 3.3 Gy; excluding 1 irradiated with 66 Gy who developed brain necrosis) were 56% (5 of 9) and 60% (6 of 10), respectively, and did not differ significantly. There were no significant differences between the 2 groups with regard to the duration of reserpine administration or pretreatment clinical features. At the latest examination, regardless of the irradiation dose, all 9 patients with long term remission showed a higher level of plasma cortisol or 11-hydroxycorticosteroids in the morning than in the evening, normal suppressibility of plasma cortisol with overnight 1 mg dexamethasone (9 of 10), and well preserved responses of other pituitary hormones to various loading tests: normal responses of plasma ACTH to CRH (6 of 9), TSH (7 of 8), and PRL (5 of 8) to TRH and age-related normal responses of GH to GRH (4 of 8), LH (6 of 8), and FSH (6 of 8) to GnRH. These findings suggest that long term reserpine administration in combination with a conventional dose of pituitary irradiation is useful in the treatment of Cushing's disease.