Osteosarcoma (OS) is the most common bone malignancy worldwide. The vascular endothelial growth factor (VEGF) gene plays an important role in the pathogenesis of OS. The objective of this study aimed to detect the potential association between VEGF genetic polymorphisms and OS susceptibility in Chinese Han population. We recruited 330 OS patients and 342 cancer-free controls in this case-control study. Three single-nucleotide polymorphisms (SNPs) (-634 G > C, +936 C > T, and +1612 G > A) of the VEGF gene were investigated by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and confirmed by direct DNA sequencing. Among these SNPs, we found that the genotypes/alleles of +936 C > T were statistically associated with the increased risk of OS (TT versus (vs.) CC: OR = 2.70, 95% CI 1.34-5.45, χ(2) = 8.2271, p = 0.0041; T vs. C: OR = 1.31, 95% CI 1.02-1.68, χ(2) = 4.3861, p = 0.0362). The T allele and TT genotype of +936 C > T could be factors that increase the risk for susceptibility to OS. The results from this study suggest that VEGF genetic variants are potentially related to OS susceptibility in Chinese Han population and might be used as molecular markers for assessing OS susceptibility.