To determine the effectiveness of triple oral antidiabetic therapy with a sulfonylurea, a biguanide, and a thiazolidinedione, we analyzed the results in 35 patients who had previously had inadequate glycemic control with a combination of glimepiride and metformin. The study cohort consisted of 27 men and 8 women (mean age, 55.8 years) who had had type 2 diabetes mellitus for a mean duration of 8.7 years. The addition of troglitazone (600 mg/day administered with the largest meal) to the glimepiride and metformin therapy yielded normal or near-normal glycemia in all 35 patients. Glycemic control was initially associated with mean weight gain; subsequently, however, mean weight was reduced to below the baseline level--perhaps attributable to the anorectic effect of metformin. Thus, for the first time, triple oral antidiabetic therapy with glimepiride, metformin, and troglitazone has been shown to be an efficacious therapeutic option for type 2 diabetes.