Background: Metformin is a commonly prescribed oral medication for the management of type 2 diabetes mellitus. It is typically used as a first-line treatment because of its effectiveness, safety profile, and relatively low cost. The present study was conducted to assess efficacy and safety of glimepiride-metformin versus glibenclamide-metformin combination in type-2 diabetics uncontrolled with metformin alone. Materials & Methods:50 patients uncontrolled type 2 diabetic patients of both genders were measured. Patients were divided into 2 groups of 25 each.Group I patients received two pills of glimepiride (1 mg)/metformin (500 mg) and group II patients received glibenclamide (5 mg)/metformin (500 mg) po once a day. Dosage was increased to a maximum of four pills in order to reach the glycemic control goals (fasting glucose ≤7.2 mmol/l, postprandial glucose b10.0 mmol/l, A1C b7%, or an A1C ≥1% reduction). Serum fasting and postprandial glucose, hemoglobin A1c (A1C), high-density lipoprotein cholesterol, and triglycerideswas compared in both groups. Results: There were 14 males and 11 females in group I and 13 males and 12 females in group II. In group I and group II, mean fasting blood sugar (mg/dl) at baseline was 174.2 and 172.6, at 4 weeks was 160.4 and 152.0, at 8 weeks was 148.4 and 134.8 and at 12 weeks was 122.6 and 120.6 in group I and group II respectively. Postprandial blood sugar(mg/dl) at baseline was 248.4and 244.6, at 4 weeks was 200.6 and 204.6, at 8 weeks was 190.2 and 194.2 and at 12 weeks was 168.4 and 182.3 in group I and group II respectively. Lipid profile (mg/dl)TC was 176.4 and 184.2, LDL- C was 92.6 and 91.8, HDL- C was 40.2 and 41.3 and TGs was 164.8 and 167.5 in group I and group II respectively. The difference was significant (P< 0.05). Nausea was seen in 3 in group I and 5 in group II, abdominal pain seen in 5and 4, metallic taste in 2 and 5 and hypoglycaemia in 2 and 4 in group I and II respectively. The difference was significant (P< 0.05). Conclusion: Glimepiride and metformin combination therapy has superior effect on PPBS level reduction and significantly lesser incidence of hypoglycaemia as compared to glibenclamide and metformin combination group.