Diabetes is one of the most common and challenging health problems. Studies in several nations show that polymorphisms within the transcription factor 7-like 2 genes could be associated with type 2 diabetes (T2D). Therefore, a case-control study was conducted to find the association between SNP rs7903146 and T2D in our population. The study consists of 110 patients referring to clinic and 80 healthy controls randomly selected based on WHO guideline. DNA was extracted from blood and genotyped by PCR-RFLP with specific primers to amplify a fragment for restriction enzyme (RsaI). A chi-square test was calculated to compare the proportions of genotypes or alleles. Using a logistic regression model, the odds ratio for risk of developing T2D was calculated with and without adjustment for age, sex, and BMI. The frequency of the T allele of rs7903146 (C/T) polymorphism was significantly higher in diabetic subjects (47.3%) compared to that in normal subjects (34.4%). Logistic regression analysis of the rs7903146 polymorphism showed that the odds ratio was 3.71(95% CI: 1.43-9.56; P: 0.008) for the TT genotype and 1.26 (95% CI: 0.67-2.39; P: 0.516) for the CT genotype when compared with the CC genotype. Odds ratio adjusted for age, sex, and BMI have shown similar results. The results show that rs7903146 of TCF7L2 gene is an important susceptibility gene for T2D mellitus in the province of Isfahan, Iran. Our results support the recent findings that rs7903146 of TCF7L2 gene is an important genetic risk factor for the development of T2D in multiple ethnic groups.