Under the activation of insulin receptors, glucose transporter 4 (Glut4) translocation is regulated by two signal transduction pathways. These pathways are the PI 3-kinase-dependent pathway and the CAP/TC10 pathway. The adaptor protein Rap guanine exchange factor 1 (RAPGEF1) also known as C3G is a component of the CAP/TC10 pathway. Defects in the RAPGEF1 protein may contribute to insulin resistance and type 2 diabetes. Recently, the RAPGEF1 gene was suggested to be involved in the development of type 2 diabetes by FUSION study. To investigate this association in the Korean population, we sequenced the RAPGEF1 gene in 24 unrelated individuals and identified 39 sequence variants. Eleven single nucleotide polymorphisms (SNPs) were selected and genotyped in 1122 Korean patients with type 2 diabetes. There were 1138 non-diabetic controls. Using a logistic regression analysis, a significant association was found between SNP rs11243444 in the RAPGEF1 gene and type 2 diabetes [OR=0.490 (95% CI 0.296-0.813), p=0.006] in the recessive model, leading the protective effect of the GG genotype on the disease development. The present study examines genetic polymorphisms in the RAPGEF1 gene, and the positive association between one polymorphism and type 2 diabetes in the Korean population.