Background: Several recent studies have shown that treatment with therapeutic lifestyle changes, and/or several drugs retard progression of prediabetes to type 2 diabetes. However, none of these studies used a Sulfonylurea (SU), although in UKPDS, SUs delayed the progression of hyperglycemia and several subjects would have been categorized as having prediabetes by present diagnostic criteria. Thus, SUs may have delayed the progression in this group as well. Objective: Therefore, we examined comparative efficacy of glimepiride and metformin in progression to diabetes in subjects with prediabetes. Methods: Twenty men and 18 women ages 28 - 81 years with prediabetes were followed for 5 - 9 years. Prediabetes was diagnosed by impaired fasting glucose and HbA1Cbetween 5.7% - 6.4% with two consecutive determinations as recommended by American Diabetes Association. Twenty obese subjects were administered metformin 500 mg/day and 18 non obese subjects received glimepiride 0.5 mg/day, in addition to dietary and exercise counseling. Results: Mean duration of follow up was 5.8 ± 0.2 years. Fasting Plasma Glucose (FPG) and HbA1Cdeclined to <100 mg/dl and <5.7% in all subjects by 6 months. During the follow up period, 9 of 20 (45%) subjects receiving metformin and 5 of 18 (27%) in glimepiride group progressed to diabetes (p < 0.01) as determined by FPG ≥ 126 mg/dl and HbA1C≥ 6.5% (RR, 1.61 with Confidence Interval, 1.43 - 1.74 for metformin vs glimepiride;p < 0.01). The mean duration to progression was 32 ± 4 months in metformin group and 47 ± 5 months in subjects receiving glimepiride. FPG and HbA1clevels promptly returned to <100 mg/dl and <5.7% on increasing daily dose of both metformin (1000 - 1500 mg) and glimepiride (2 - 4 mg). The glycemic control was maintained till the end of observation period. None of the subjects in either group manifested a cardiovascular event nor any of the subjects died during the period of observation. Conclusion: Glimepiride may be more effective in delaying the progression of prediab