Efficacy of sulfonylurea in combination with either metformin or troglitazone was investigated in 34 patients with non-insulin dependent diabetes mellitus (NIDDM) without serious diabetic complications. The patients were aged from 48 to 78 yr (mean±SD : 63.9±8.1) with a diabetic history of 5 to 9 yr, in which glycemic control by sulfonylurea alone was unsatisfactory with elevated HbA1c levels (8.0±1.0%). They were assigned to the combination therapy with sulfonylurea and either metformin (750mg/day) (group 1,n=19) or troglitazone (400mg/day) (group 2,n=15) for three months. The baseline characteristics did not differ between groups 1 and 2 before the therapy. In group 1,fasting plasma glucose (FPG) decreased from 147.5±29.4mg/dl to 119.7±24.2ng/ml (P<0.001) and hemoglobin A1c (HbAlc) decreased from 7.9±1.2% to 6.5±0.7% after the combination therapy for three months. In group 2,FPG and HbA1c were also decreased from 161.8±25.4mg/dl to 134.7±20.0mg/dl (P<0.05) and from 8.0±0.7% to 7.2±0.7% (P<0.001), respectively. HbA1c levels were more reduced in group 1 than in group 2 (P<0.02). Fasting plasma C-peptide (CPR) levels were more reduced (P<0.02) in group 2 (from 2.6±0.5 to 1.1±0.5ng/ml, P<0.001) than in group 1 (from 2.7±1.0ng/ml to 1.4±0.5ng/ml, P<0.001). Body mass index (BMI) was decreased in groupl (from 26.1±3.6 to 25.7±3.3,P<0.05) whereas it was not changed in group 2 after the treatment for three months. These findings suggest that sulfonylurea in combination with either metformin or troglitazone is effective for better glycemic control in patients with NIDDM which are not well controlled by sulfonylurea alone, and that metformin is more effective to reduce BMI whereas troglitazone is more effective to reduce plasma CPR without changing BMI in these patients.