Type 2 diabetes is a common complex disorder with environmental and genetic components. The aim of the present study was to investigate the association between the polymorphisms of RAPGEF1, TP53 and NRF1 and the risk of type 2 diabetes in the Chinese Han population. We genotyped rs11243444 (RAPGEF1), rs1042522 (TP53) and rs1882095 (NRF1) in a case-control study, including 273 type 2 diabetes and 247 healthy controls. A significant association was found in a variant of TP53 (rs1042522, odd ratio (OR)=1.28, 95% confidence interval (CI)=1.00-1.64; P=0.046), whereas polymorphisms in RAPGEF1, NRF1 were not associated with the risk of type 2 diabetes. Furthermore, a potential gene-gene interaction showed the odds of being affected with type 2 diabetes was 2.54 times greater in subjects with the TP53 (rs1042522) and RAPGEF1 (rs11243444) risk alleles than those without either (95% CI=1.34-4.81; P=0.004) and the NRF1 gene polymorphism reached significance when paired with TP53:(OR=3.87, 95% CI=1.87-8.40; P=0.0006). We demonstrated that the polymorphism in TP53 (rs1042522) was associated with type 2 diabetes, and that potential interaction of TP53 (rs1042522) and RAPGEF1 (rs11243444), or NRF1 (rs1882095) increased the risk of type 2 diabetes.