The aim of the study was to explore the correlation between rs7903146 and rs290487 polymorphisms in transcription factor 7-like 2 (TCF7L2) gene and diabetic nephropathy (DN) in Chinese Han population.Polymerase chain reaction-restriction fragment length polymorphism was used to determine genotypes of TCF7L2 polymorphisms in 90 patients with DN and 96 diabetes patients without DN. The linkage disequilibrium (LD) and haplotype analysis were performed with haploview software. Hardy-Weinberg equilibrium was assessed in the control group based on the genotype distributions of TCF7L2 polymorphisms. The genotype, allele, and haplotype distribution differences between the case and control groups were analyzed by chi-squared test, and odds ratio (OR) and 95% confidence interval (CI) were used to indicate the relative risk of DN.People carrying TT genotype of rs7903146 were more easily to be attacked by DN than CC genotype carriers (P = .02, OR = 4.26, 95% CI = 1.12-16.24). Meanwhile, T allele also showed 1.85 times risk to suffer from DN compared with C allele (OR = 1.85, 95% CI = 1.02-3.10). However, there was no significant difference in genotypes and alleles frequencies of rs290487 between 2 groups. The strong LD existed between the 2 single nucleotide polymorphisms and haplotype T-T (rs7903146-rs290487) increased the susceptibility to DN (OR = 2.63, 95% CI = 1.31-5.25).TCF7L2 rs7903146 polymorphism may be associated with the susceptibility to DN in Chinese Han population, but rs290487 is not. Additionally, haplotype is also a risk factor for DN.