Background Retinopathy is one of the major causes of visual impairment which is the most severe microvascular complication of diabetes mellitus (DM). The aim of this study was to evaluate the association between diabetic retinopathy (DR) and two SNPs (− 152G > A and − 165C > T) located in the promoter region of the vascular endothelial growth factor (VEGF) gene in a small sample from Egyptian population. One hundred diabetic patients without retinopathy (DWR) and two hundred diabetic patients with retinopathy were included in this study. Genotype analysis for the two SNPs (− 152G > A and − 165C > T) was assessed by using the PCR–RFLP technique. In addition, the serum protein level of VEGF was measured by ELISA assay. Results The results showed a significant relationship between − 152G > A (rs13207351) polymorphism and both proliferative and non-proliferative retinopathy in genotypes (GG, GA, AA). The risk factor increment in the mutant heterozygous genotype (GA) was significantly increased in NPDR compared to PDR (OR = 16.3, 95%CI = 0.80–331.7); (OR = 20.4, 95%CI = 1.08–385.3), respectively. There was no significance between VEGF − 165C > T (rs79469752) gene polymorphism and retinopathy. Moreover, the serum protein level of VEGF showed a highly significant increase (P = 0.0001) in PDR (Mean ± SD = 3691 ± 124.9) when compared to both DWR (Mean ± SD = 497.3 ± 18.51) and NPDR (Mean ± SD = 1674.5 ± 771.7). These results were supported by the increased level of VEGF in serum protein which is positively correlated with the severity of retinopathy. Measuring VEGF protein level in DR patients would help as a biomarker in early diagnosis. Conclusion The increase in the mutant heterogeneous GA genotype in VEGF − 152G > A SNP could be a risk factor for the progression of severe retinopathy in diabetic patients.