Background: Type 2 diabetes (T2D), is also known as adult-onset diabetes, it is characterized by raised in blood glucose levels, insulin resistance, and relative lack of insulin. Most of the cases of diabetes is due to gene polymorphism, the transcription factor-7-like 2 (TCF7L2) gene has been found as the most important gene to cause type 2 diabetes mellitus (T2DM). The main aim of the study is to study the effect of mono drug therapy in TCF7L2 gene associated type 2 diabetes mellitus. Material and Methods: Prospective, randomised study. Group A- Metformin and Group B - Glimepride. Results: TCF7L2 gene is associated with Type 2 diabetes mellitus. Genetic investigation was done in all 20 patients three genotypes have been identified CC, CT and TT genotypes in both the groups. Baseline values are higher in TT genotype when compared with CT & CC genotypes. In all group there is a significant improvement in blood glucose levels were as a controlled lipid profile was observed in CC genotype of Group A but no significant was observed in CT, TT and in group B genotypes. Conclusion: Patients HbA1c ranges from 6.5 to 7.5 % prescribed with mono drug therapy of metformin and Glimepride shows significant improvement in blood glucose levels in all three genotypes but no significant was observed in CT, TT and Glimepride treated groups. As a result metformin is the better drug of choice in CC genotype associated type 2 diabetes mellitus when compared with Glimepride.