OBJECTIVE: To evaluate the safety and effectiveness of rosiglitazone in the treatment of overweight subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 50 adult type 1 diabetic subjects with a baseline BMI > or =27 kg/m(2) were randomly assigned in a double-blind fashion to take insulin and placebo (n = 25) or insulin and rosiglitazone 4 mg twice daily (n = 25) for a period of 8 months. Insulin regimen and dosage were modified in all subjects to achieve near-normal glycemic control. RESULTS: Both groups experienced a significant reduction in HbA(1c) (A1C) level (rosiglitazone: 7.9 +/- 1.3 to 6.9 +/- 0.7%, P < 0.0001; placebo: 7.7 +/- 0.8 to 7.0 +/- 0.9%, P = 0.002) and a significant increase in weight (rosiglitazone: 97.2 +/- 11.8 to 100.6 +/- 16.0 kg, P = 0.008; placebo: 96.4 +/- 12.2 to 99.1 +/- 15.0, P = 0.016). Baseline measures of BMI (P = 0.001), total daily insulin dose (P = 0.002), total cholesterol (P = 0.005), HDL cholesterol (P = 0.001), and LDL cholesterol (P = 0.02) were predictors of improvement in A1C level only in the group treated with rosiglitazone. Total daily insulin dose increased in subjects taking placebo (74.0 +/- 33.8 to 82.0 +/- 48.9 units, P < 0.05 baseline vs. week 32), but it decreased slightly in subjects taking rosiglitazone (77.5 +/- 28.6 to 75.3 +/- 33.1 units). Both systolic blood pressure (137.4 +/- 15.6 vs. 128.8 +/- 14.8 mmHg, baseline vs. week 32, P < 0.02) and diastolic blood pressure (87.2 +/- 9.4 vs. 79.4 +/- 7.2 mmHg, P < 0.0001) improved in the group treated with rosiglitazone. The total incidence of hypoglycemia did not differ between groups. CONCLUSIONS: Rosiglitazone in combination with insulin resulted in improved glycemic control and blood pressure without an increase in insulin requirements, compared with insulin- and placebo-treated subjects, whose improved glycemic control required an 11% increase in insulin dose. Weight gain and hypoglycemia were similar in both groups at the end of the study. The greatest effect of rosiglitazone occurred in subjects with more pronounced markers of insulin resistance.