This study evaluated the efficacy and safety of rosiglitazone mono- therapy in patients with type 2 diabetes. After a 4-week placebo run-in period, 493 patients with type 2 diabetes were randomized to receive rosiglitazone (2 or 4 mg twice daily (bd)) or placebo for 26 weeks. The primary end point was change in hemoglobin A1c; other variables assessed included fasting plasma glucose, fructosamine, endogenous insulin secretion, urinary albumin excretion, serum lip- ids, and adverse events. Rosiglitazone (2 and 4 mg bd) decreased mean hemoglobin A1c relative to placebo by 1.2 and 1.5 percentage points, respectively, and reduced fasting plasma glucose concentrations rel- ative to placebo by 3.22 and 4.22 mmol/L, respectively. Fasting plasma insulin and insulin precursor molecules decreased signifi- cantly. Homeostasis model assessment estimates indicate that ros- iglitazone (2 and 4 mg bd) reduced insulin resistance by 16.0% and 24.6%, respectively, and improved b-cell function over baseline by 49.5% and 60.0%, respectively. Urinary albumin excretion decreased significantly in the rosiglitazone (4 mg bd) group. There was no in- crease in adverse events with rosiglitazone. In the short-term, ros- iglitazone is an insulin sensitizer that is effective and safe as mono- therapy in patients with type 2 diabetes who are inadequately controlled by lifestyle interventions. (J Clin Endocrinol Metab 86: 280 -288, 2001)