Effects of reserpine treatment, not associated with pituitary irradiation, on the pituitary-adrenocortical axis in a total of 37 untreated patients with Cushing's disease were evaluated. With short-term treatment (2mg daily for 2 weeks, n=36), basal excretion of urinary 17-OHCS significantly decreased from 11.2±5.2mg/day/m² (body surface area) (mean ±SD) to 9.6±4.4mg/day/m² (P<0.01), and metyrapone-induced incremental responses of urinary 17-OHCS decreased from 58.4±41.4mg/³ days/m² to 45.9±29.8 mg/3 days/m² (P<0.05). Long-term treatment (1.7±0.3mg/day for a mean of 15.8±19.9 weeks) induced a marked reduction in plasma cortisol, and 24-h urinary 17-OHCS and/or free cortisol in 4 of 8 patients examined. Long-term reserpine administration caused normal suppression of plasma cortisol (or 11-OHCS) in 3 of 9 patients with 1mg, and in all of 5 patients with an 8mg overnight dexamethasone suppression test. Plasma ACTH response to CRH was evidently decreased in one patient evaluated one month after the initiation of reserpine. The circadian rhythm of plasma cortisol was normal in one patient when the basal glucocorticoid level became normal with reserpine treatment. The present findings suggest that reserpine itself contributes in a causal fashion to the effectiveness of our regimen, reserpine and pituitary irradiation, for some Cushing's disease patients in whom it is effective.