Background: Type 2 diabetes mellitus (T2DM) is the most prevalent component of metabolic syndrome. Environmental factors and various complex genes like transcription factor 7-like 2 (TCF7L2) gene have involved in the disease development. Objective: To determine TCF7L2 genetic association (rs7903146C/T and rs12255372G/T) in T2DM patients of Khyber Pakhtunkhwa population of Pakistan. Subjects and methods: This study comprised of 176 subjects including 118 T2DM patients and 58 healthy controls. Genomic DNA was extracted and genotype of common variants (rs7903146 C/T and rs12255372 G/T) was carried out by amplification-refractory mutation system (ARMS)-PCR of sequence specific oligonucleotides. Results: The distribution of genotype of TCF7L2 SNPs (rs7903146 C/T and rs12255372 G/T) was significantly associated with T2DM as compared to the controls (p <0.0001). The genetic models of the rs7903146 (C/T) and rs12255372 (G/T) SNPs were significantly associated between cases and controls (p <0.0001). On the other hand, the significant association was observed between the two SNPs and different biochemical parameters like serum fasting glucose, lipid profile, creatinine and blood HbA1c levels (p <0.05). Conclusion: It is concluded that the SNPs of the TCF7L2 gene are significantly associated with T2DM disease susceptibil- ity in the population of Khyber Pakhtunkhwa of Pakistan. Keywords: T2DM; TCF7L2; Genetic association, ARMS-PCR, Single nucleotide Polymorphism (SNPs), Khyber Pakh- tunkhwa.