Diabetic retinopathy and nephropathy cause significant morbidity in patients with diabetes. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor and is implicated in both of these diabetes complications. We previously reported transfection studies showing the VEGF -460 and VEGF +405 polymorphisms to increase basal VEGF promoter activity by 71% compared with the wild-type sequence. Therefore, we investigated the association of these VEGF polymorphisms with proliferative diabetic retinopathy and diabetic nephropathy. DNA was isolated from 267 U.K. Caucasians with diabetes, comprising 69 patients with proliferative retinopathy and 198 patients with other grades of retinopathy. The distribution of VEGF -460 genotype was significantly different between the proliferative retinopathy and nonproliferative retinopathy groups (P = 0.027); specifically, carriage of the VEGF -460C allele was associated with proliferative diabetic retinopathy (odds ratio 2.5 [95% CI 1.20-5.23]). The VEGF -460 genotype was predictive of retinopathy, even after controlling for blood pressure, glycemic control, duration of diabetes, and obesity (P = 0.02). The VEGF +405 genotype did not associate with proliferative retinopathy, and neither polymorphism was associated with diabetic nephropathy. The VEGF -460C polymorphism is a positive independent predictive factor for the development of proliferative diabetic retinopathy. Increased VEGF production from high-expressing haplotypes, including -460C, may promote neovascularization.