Patterning of plasma ACTH, beta-EP/beta-LPH and cortisol in response to ovine CRF (1 microgram/kg b.w.t. injected i.v.), was studied in three normal subjects and in five patients with Cushing's disease, two of whom had undergone total bilateral adrenalectomy. CRF caused in all subjects a prompt and concurrent rise of plasma hormone levels. The hormonal response was of the same magnitude in normal controls and in the three untreated Cushing's patients, but was much greater in the two adrenalectomized subjects. No changes were noted, after CRF, in plasma levels of GH, PRL, TSH, LH and FSH. These findings indicate that CRF specifically promotes the pituitary release of ACTH and ACTH-related peptides both in normal subjects and patients with Cushing's disease. In view of the likely CRF hypersecretion of the adrenalectomized patients, their ACTH and beta-EP/beta-LPH hyperresponsiveness to exogenous CRF would denote that the peptide does not down regulate its own pituitary receptors.