Background: There are subgroups of patients with diabetes mellitus (DM) in whom diabetic retinopathy (DR) does not develop despite poor long-term control of their disease, while others exercising fairly good control, develop retinopathy. So, we aimed to investigate the association of DR with −2578 polymorphism of the vascular endothelial growth factor (VEGF) gene, which has been reported to be associated with increased VEGF production, in Egyptian diabetic patients.Materials and Methods: This is a case control study in which 148 diabetic patients were enrolled. Among them, 44 subjects had proliferative diabetic retinopathy (PDR), 30 had non-proliferative diabetic retinopathy (NPDR), and 74 individuals without retinopathy served as controls. A single nucleotide polymorphism (SNP) of the VEGF gene, a C→A transversion at −2578 (the C/A polymorphism), was investigated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).Results: We found a higher frequency of the polymorphic genotype in both the NPDR (66.7%) and PDR (72.7%) groups compared to the wild C/C genotype (33.3% in NPDR and 27.3% in PDR), but with no statistically significant difference from the control group. Significant association of the progression of DR to the polymorphic genotype was achieved at diabetes duration more than 20 years.Conclusion: Despite of the higher frequency of both the polymorphic genotype and the A allele in cases with DR compared to the control group, there might be no significant association between the VEGF gene polymorphism and DR per se, unless it is longstanding.