Suppression of pituitary-adrenal function is a well-known consequence of glucocorticoid therapy, manifested principally by decreased corticotropin secretion. To determine the degree of suppression of pituitary-adrenal function in patients treated with different doses of synthetic glucocorticoid medication for different periods, we measured the pituitary-adrenal response to the administration of exogenous human corticotropin-releasing hormone (CRH). We studied 279 patients who were receiving daily therapy with 5 to 30 mg of prednisone or its equivalent to treat various chronic diseases, principally collagen vascular disorders, and 50 normal subjects. Therapy ranged in duration from 1 week to 15 years. Stimulation tests using 100 micrograms of CRH as a bolus injection were performed in the morning, 24 hours after the most recent dose of glucocorticoids. In 61 patients an insulin hypoglycemia test, thought by many to be the reference standard, was also performed to assess the reliability of the CRH results. After the administration of CRH, 43 patients had no increase in plasma concentrations of corticotropin and cortisol. The response was blunted in 133 patients and normal in 103. There was poor correlation between the plasma cortisol response after the administration of CRH and the dose or duration of therapy or the basal plasma cortisol concentration. Although plasma cortisol concentrations after stimulation with CRH were generally lower than those after insulin administration, there was a significant correlation between the plasma cortisol responses to the two stimuli (r = 0.82). Pituitary-adrenal function in patients treated with synthetic glucocorticoids cannot be reliably estimated from the dose of glucocorticoid, the duration of therapy, or the basal plasma cortisol concentration. In such patients, testing with CRH is nearly as useful as insulin hypoglycemia testing in the assessment of pituitary-adrenal function.