Ten patients with adrenal insufficiency receiving chronic glucocorticoid therapy were studied. All had subnormal plasma cortisol responses to ovine corticotropin-releasing hormone ( CRH ) (1 microgram/kg as an iv bolus) 12-60 h after discontinuation of steroid treatment. Plasma ACTH responses to CRH fell into three different patterns. The first three patients with primary adrenal insufficiency had high basal ACTH levels and augmented ACTH responses to CRH . A fourth such patient, however, treated with pharmacologic doses of prednisone, had a low normal ACTH response. Patients with secondary adrenal insufficiency had either low basal ACTH levels and diminished responses to CRH or low basal ACTH values but prolonged and augmented plasma ACTH responses to CRH with a delayed peak. We postulate that the group of patients with the former pattern have pituitary gland destruction whereas the patients with the latter pattern have hypothalamic CRH deficiency. Thus, CRH may be useful in differentiating between hypothalamic and pituitary causes of adrenal insufficiency.