Glimepiride is a new once-daily sulfonylurea. Animal studies have shown that it lowers blood glucose through extrapancreatic process. The aim of our study is to observe the effect of glimepiride on glycemic control, body weight change and insulin levels during fasting. Thirty two Type 2 diabetic patients, whose blood glucose levels cannot be controlled adequately with diet and exercise alone, received a 12-week course of glimepiride treatment. They were followed up after 2 weeks, 4 weeks, 8 weeks and 12 weeks. Their fasting, two-hour postprandial blood glucose and body weight were recorded during each visit. Hemoglobulin A1c (HbA1c) and fasting insulin levels were measured at the beginning and end of the study. Fasting plasma glucose (FPG), two-hour postprandial plasma glucose (PPG) and HbA1c values decreased significantly after treatment. The paired mean FPG decreased from 237 ± 66.58 mg/dL to 149 ± 41.31 mg/dL (P ≤ 0.001), PPG from 352 ± 112.44 mg/dL to 159 ± 22.86 mg/dL (P ≤ 0.001) and HbA1c from 11.04 ± 2.91% to 6.98 ± 1.52% (P ≤ 0.001). In contrast, fasting insulin levels and body weight did not have meaningful differences at 0 week and 12 weeks. mThe paired mean fasting insulin level increased from 13.19 ± 1.52 μIU/mL to 16.76 ± 9.48 μIU/mL (P = 0.594). The paired mean body weight increased from 65.01 ± 8.94 kg at baseline to 68.25 ± 9.80 kg at endpoint (P = 0.023). Glimepiride lowers blood glucose effectively without much effect on fasting insulin levels and body weight gain. These results suggested that glimepiride lowers blood glucose not only by stimulating insulin secretion but also by its extrapancreatic effects. This metabolic effect is desirable because hyperinsulinemia increases body weight, atherosclerosis and risk of hypoglycemia in diabetic patients.