Background: Transcription factor 7-like 2 (TCF7L2) gene polymorphisms are known risk factors for type 2 diabetes mellitus (T2DM). However, the relationship between TCF7L2 polymorphism and diabetic nephropathy (DN) is inconclusive. Objectives: to explore the association of TCF7L2 rs7903146 (C/T) gene polymorphism and DN in T2DM  Egyptian patients. Methods: 80 patients with T2DM (40 patients without DN and 40 patients with DN) were enrolled in the study. Genotyping for the rs7903146 (C/T) polymorphism in TCF7L2 gene was performed by real time PCR.
Results: The frequency of rs7903146 genotypes in diabetic patients without DN was ( CC: 57.5%; CT: 37.5%; TT: 5%), while in diabetic patients with DN was (CC: 2.5%; CT: 40%; TT: 57.5%). Patients with DN were exposed to the TT 25.7 times more than who didn't develop DN  (OR= 25.7, 95% CI= 0.43-94, P= 0.001**). Upon examining the allelic discrimination, C allele was present in 77.5%  of patients without DN versus 23.8%  of patients with DN, While T allele was found in 22.5%  of patients without DN versus 76.3%  of patients with DN. Patients with DN were exposed to the T allele  11 times more than who didn't develop nephropathy (OR=11, 95% CI= 5.3-23.1 , P=<0.001**). Conclusion: rs7903146 TCF7L2 gene polymorphism may be significantly associated with the susceptibility to DN in Egyptian T2DM patients.