The aim of the study was to compare the long-term effect of 4 antidiabetic treatment protocols on insulin resistance evaluated by euglycemic hyperinsulinemic clamp in type 2 diabetes mellitus patients. Two hundred seventy-one type 2 diabetes mellitus patients with poor glycemic control and who were overweight were enrolled in this study. Patients were randomized and titrated to take pioglitazone, metformin, pioglitazone + metformin, or glimepiride + metformin for 15 months. They underwent a euglycemic hyperinsulinemic clamp at baseline, after 3 months, and after 15 months. Anthropometric and metabolic measurements were assessed at baseline, after 3 months, and after 15 months. There was a decrease in glycated hemoglobin in all groups, but glycated hemoglobin value was lower in the group treated with pioglitazone + metformin compared with the groups treated with metformin alone and with pioglitazone alone. There was a decrease in fasting plasma glucose and postprandial plasma glucose values in all groups, but values obtained with pioglitazone + metformin were lower compared with values in the groups treated with metformin alone and with pioglitazone alone. Fasting plasma insulin and postprandial plasma insulin values were higher in the group treated with glimepiride + metformin compared with the other groups. After 15 months, glucose infusion rate and total glucose requirement values observed in the groups treated with pioglitazone alone and with pioglitazone + metformin were higher compared with the values in the group treated with metformin alone and with glimepiride + metformin; furthermore, values obtained in the group treated with pioglitazone + metformin were higher than the value obtained with pioglitazone alone. Pioglitazone-metformin-based therapeutic control is associated with the most quantitatively relevant improvement in insulin resistance-related parameters, whereas the sulfonylurea-metformin-including protocol has less relevant effects.