Background: Type 2 diabetes is a chronic disease that usually requires treatment with multiple antihyperglycemic agents (AHAs) during the course of the disease. Sulfonylureas (SUs) are frequently used in treatment in approximately 60% of type 2 diabetes patients. However, SUs often increase the risks of hypoglycemia and weight gain resulting in deterioration of glycemic control in the long term. Aims and Objectives: To evaluate the efficacy and safety of sitagliptin in comparison with glimepiride in treatment of T2DM inadequately controlled with metformin alone. Materials and Methods: Hundred T2DM patients were studied patients at the Department of Medicine and Department of Pharmacology, L N Medical College and research center Bhopal after dividing them in to Group A (n=50, patients receiving glimepiride) and Group B (n=50, patients receiving sitagliptin).Treatment was provided for the period of 18 weeks and patients were called for follow up at the end of 4, 12, 18 weeks (3 follow ups). Primary endpoint: Change from baseline at 18 weeks in HbA1C. Secondary endpoint: change from baseline at 18 weeks fasting blood sugar level; change from baseline at 18 weeks post prandial sugar level and any reported adverse event were recorded. Result: Mean age of study population of Group A and Group B was 46.17±10.37 years and 49.87±11.24 years respectively (p=0.198). Maximum patients in Group A and Group B were female [31 (62%) and 30 (60%) respectively] (p>0.05). Percentage reduction in HbA1c in Group A and Group B at 4^th, 12^th, and 18^th week was 2.40% vs. 3.38, 4.18% vs. 4.34 and 4.75% vs. 3.40% respectively (p>0.05). Percentage reduction in FPG in Group A and Group B at 4^th, 12^th, and 18^th week was 19.89% vs. 12.60, 9.57% vs. 21.26 and 16.80% vs. 13.72% respectively (p>0.05).Percentage reduction in PPG in Group A and Group B at 4^th, 12^th, and 18^th week was 16.85% vs. 18.26%,, 22.44% vs. 21.06 and 12.18% vs. 11.57% respectively (p>0.05). Change in body weight observed in Group A was of 1.72 kgs (64.54±7.8 kg baseline Vs 66.26±8.12 kg at 18^th week; p<0.008) whereas among Group B population mean change was -1.69 kg (62.16±7.12 kg at baseline Vs 60.47±6.56 kgs at 18^th week follow up; p<0.011). In Group A and Group B, 24% and 18%) reported adverse drug reaction. Conclusion: Sitagliptin could be a better alternative to glimepiride in combination with metformin.