Background:An oral drug called metformin is frequently recommended for the treatment of type 2 diabetes mellitus. Its efficacy, safety record, and affordability make it the therapy of choice for most patients.Materials & Methods:120 uncontrolled type II diabetic patients of both genders were divided into two groups of 60 patients each. Patients in group I were given two pills of glimepiride (1 mg)/metformin (500 mg), while patients in group II were given one daily dose of glibenclamide (5 mg)/metformin (500 mg).Results: The mean fasting blood glucose (mg/dl) at baseline was 178.2 and 176.6, at 4 weeks was 166.4 and 156.0, and at 8 weeks was 152.6 and 138.8 in group I and group II respectively. Postprandial blood glucose (mg/dl) at baseline was 252.4 and 230.6, at 4 weeks was 206.2 and 208.4, and at 8 weeks was 180.4 and 198.2 in group I and group II respectively. Lipid profile (mg/dl) TC was 176.4 and 188.2, LDL- C was 96.6 and 95.8, HDL- C was 46.2 and 45.3 and TGs was 168.8 and 171.5 in group I and group II respectively. The difference was significant (P< 0.05). Adverse events were nausea seen in 2 in group I and 4 in group II, metallic taste in 4 in group I and 3 in group II, hypoglycemia in 3 in group I and 5 in group II, and abdominal pain seen in 1 in group I and 3 in group II.Conclusion: When compared to the glibenclamide and metformin combination group, glimepiride and metformin combination therapy has a superior effect on post-prandial blood glucose level reduction and a considerably lower incidence of hypoglycemia.