Objective: Type 2 diabetes mellitus (T2DM) has a multifactorial etiology involving a complex interplay between genes and the environment. The prevalence of T2DM among the countries of the Gulf Corporation Council (GCC), including the United Arab Emirates (UAE), ranks among the top 15 in the world. A number of studies have shown an increase in T2DM risk for the “TT” genotype at the rs4506565 and rs12255372 Single Nucleotide Polymorphisms (SNP) of the TCF7L2 gene. However, the association between TCF7L2 and T2DM still needs to be investigated in the UAE population. Therefore, this study analyzed the potential associations with rs4506565 and rs12255372 in UAE subjects. Methods: For this case-control study, T2DM patients (n = 890) and healthy subjects (n = 686) were genotyped using a Taqman Real-Time PCR assay. Statistical analysis was performed with the resulting data using the R (version 3.3.1) and STATA (version 13) software packages. Results: The rs12255372 SNP was significantly associated with T2DM (OR = 1.16, 95% CI = 1.00-1.34; P =.042). However, no significant association was found for the rs4506565 SNP (P =.120). After gender stratification, a significant association was found for both SNPs in males (Prs4506565 =.009 and Prs12255372 =.021). Interestingly, we found the interaction between the SNP rs4506565 with gender alone (P =.032) and in conjunction with BMI and age (P =.036) confers associations with T2DM. Conclusions: These findings suggest that the genetic variants of the TCF7L2 gene are associated with an increased susceptibility to T2DM, especially in Emirati males. Our study also highlights the impact of biological and environmental risk factors including age, BMI, and gender on the genetic susceptibility to T2DM.