Background: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. Objective: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS. Design: This was designed as a retrospective, multicenter study. Setting: Thirteen University hospitals were studied. Patients: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3). Measurements: Measurements included biochemical parameters of activity of CS: mean serum cortisol “day-curve” (CDC) (target 150–300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC). Results: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L 26.2 μg/dL vs 348.6 nmol/L 12.6 μg/dL; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L 32.0 μg/dL vs 491.1 nmol/L 17.8 μg/dL; P < .0001); and UFC (37 patients, 1483 nmol/24 h 537 μg/24 h vs 452.6 nmol/24 h 164 μg/24 h; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 μg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 μg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible. Conclusions: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS.