Subnormal plasma 11-deoxycortisol (compound S) responses to metyrapone were found in patients with adrenal insufficiency or with Cushing syndrome caused by adrenal tumors and in those receiving long-term glucocorticoid or diphenylhydantoin sodium therapy. High normal or exaggerated responses were seen in women receiving oral contraceptives, patients with Cushing syndrome caused by adrenal hyperplasia, and those with untreated hypothyroidism. Diabetes mellitus, hypoglycemia, congestive failure, and obesity also were associated with exaggerated responses. Subnormal plasma S responses were observed in 15 patients who responded normally to a repeat test or to the standard metyrapone test. The abnormal response resulted from insufficient metyrapone, administration at the wrong time, or delay in obtaining the blood sample. The single-dose metyrapone test may be the procedure of choice in screening for adrenal insufficiency.