Polymorphisms of the endothelial nitric oxide synthase (eNOS) gene have been implicated in various diseases, but their roles as risk factors in type 2 diabetes mellitus (T2DM) with regard to coronary artery disease (CAD) are largely unknown. Therefore, we investigated the association of the genotypes and haplotypes of eNOS polymorphisms in CAD with T2DM. A case-control study was performed to evaluate the genotypes and haplotypes of the eNOS polymorphisms (-786T>C, 4a4b and 894G>T) in 192 CAD patients and 196 controls. The same population was also re-organized upon the status of T2DM. The genotypes of eNOS -786T>C, 4a4b and 894G>T polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism. We found that eNOS -786TC+CC and 4a4b+4a4a genotypes were significantly prevalent in the diabetic controls and the diabetic CAD patients compared to the non-diabetic controls or non-diabetic CAD patients, respectively. The frequency of the -786C-4a-894G haplotype was significantly greater in the diabetic CAD patients (p=0.001) and diabetic controls (p=0.023) compared to the non-diabetic controls, whereas the haplotype of -786T-4b-894G was less prevalent in the diabetic CAD patients compared to the non-diabetic controls (p=0.018). Significant associations of the genotypes and the haplotypes were consistently observed in the T2DM group compared to non-DM group, regardless of CAD status. Our finding suggests that the eNOS -786T>C and 4a4b polymorphisms and the -786C-4a-894G haplotype are risk factors for T2DM, whereas the haplotype of -786T-4b-894G has a protective effect against the development of T2DM.