Objective: To investigate the relationship between vascular endothelial growth factor (VEGF) gene polymorphisms and Retinopathy of prematurity (ROP) development in preterm infants of China Han ethnic population. Methods: VEGF gene promoter polymorphisms (-165C/T and -141A/C) were studied in 54 neonates with ROP but not requiring treatment (regressive ROP group), 48 neonates with ROP that requires cryotherapy/photocoagulation (severe ROP group), and in a control group of 62 preterm infants without ROP. Genotyping for VEGF gene promoter was performed by polymerase chain reaction (PCR) and gene sequencing. Results: In this study, -165C/T genotype was found to be associated with severe ROP (P=0.012 < 0.05), but not with regressive ROP. For the dominant genetic model, subjects carrying the -165T allele had a decreased risk of ROP compared to those non-carrying the -165C allele in both regressive ROP regressive group and severe ROP group, and especially in severe ROP group (in regressive ROP group: OR=2.069, 95% CI=0.986-4.340; in severe ROP group: OR=3.677, 95% CI=1.339-10.099). For the allelic model, comparing the A allele to the C allele, the -165C/T site also showed a decreased risk of ROP in both regressive ROP group and severe ROP group (in regressive ROP group: OR=2.395, 95% CI=1.112-5.157; in severe ROP group: OR=4.258, 95% CI=1.518-11.945). In -141A/C genotypes and alleles were found not to be associated with severe ROP or regressive ROP. Linkage disequilibrium analysis revealed -165C/T and -141A/C were a strong linkage disequilibrium, and haplotype analysis revealed that T -165 C -141 haplotype was associated with resistance to severe ROP but C -165 A -141 haplotype was associated with risk to severe ROP. No statistically significant differences were observed in regressive ROP group. Conclusion: VEGF -165C/T SNP is associated with ROP especial in severe ROP. VEGF -141A/C SNP is not associated with ROP. T -165 C -141 and C -165 A -141 haplotypes may have a role in severe ROP.