Patients with congenital adrenal hyperplasia (CAH) are chronically treated with supraphysiological doses of glucocorticoids, which are known to induce insulin resistance. Thiazolidinediones might reverse this effect and improve insulin sensitivity.To assess insulin sensitivity in CAH patients and the effect of pioglitazone treatment on insulin sensitivity in CAH patients. Secondary objectives were the effects of treatment with pioglitazone on blood pressure, body fat distribution, lipid, and steroid profiles.Randomized placebo controlled crossover trial.Twelve CAH patients and 12 body mass and age-matched control subjects.Sixteen-week treatment with pioglitazone (45 mg/day) or placebo.Insulin sensitivity measured by euglycemic clamp and oral glucose tolerance test. Further measures were 24-h blood pressure profiles, body fat distribution measured by magnetic resonance imaging, dual energy x-ray absorptiometry (DEXA) and bioimpedance procedures, liver fat by magnetic resonance spectroscopy, lipid, and steroid profiles.CAH patients were insulin resistant compared with healthy controls. Treatment with pioglitazone significantly improved insulin sensitivity in CAH patients (glucose infusion rate (GIR) from 28.5+/-11.6 to 38.9+/-11.0 micromol/kg per min, P=0.000, GIR in controls 46.2+/-23.4 micromol/kg per min, P<0.05 versus CAH). Treatment with pioglitazone decreased blood pressure (systolic: 124.0+/-13.6 vs 127.0+/-14.9 mmHg, P<0.001, diastolic: 72.8+/-11.5 vs 77.4+/-12.6 mmHg, P<0.001). No changes in body fat distribution, lipid, and steroid profiles were observed.CAH patients are insulin resistant compared with matched control subjects. Treatment with pioglitazone improves insulin sensitivity and decreases blood pressure in CAH patients.