Genetic factors are important in the pathogenesis of diabetic retinopathy (DR); there is a clear association of increased expression of vascular endothelial growth factor (VEGF) with DR as well as numerous VEGF polymorphisms that are linked to increased VEGF levels and DR. In this study, the relationships between the VEGF promoter polymorphism -634C/G, plasma VEGF levels and DR were examined in the Han Chinese. Ninety-six healthy subjects and 285 subjects with type 2 diabetes were enrolled in this study. The diabetic subjects were divided into three groups depending on the degree of DR as determined by fundus photography and fluorescent angiography. Along with standard clinical characteristics, the -634C/G polymorphism was examined using TaqMan allelic discrimination, and plasma VEGF levels were analyzed by enzyme-linked immunosorbent assay. The distribution of the polymorphism differed significantly between patients with and without retinopathy; this was most pronounced between the no DR and proliferative DR groups. Significantly greater plasma VEGF levels were present in those with the -634CC genotype, and only the proliferative DR group had elevated plasma VEGF levels. Logistic regression revealed that the -634C/G polymorphism is strongly associated with DR. This study suggests that diabetic Han Chinese carrying the -634CC VEGF promoter polymorphism have a genetic risk of DR, and this polymorphism may be a major factor influencing plasma VEGF levels. Therefore, this polymorphism may be used as a biomarker at the onset of diabetes in the Han Chinese to predict the risk of DR, allowing for clinicians to treat these patients more aggressively.