Previous studies suggest that the MDM2 gene is one of the most important candidate genes for influencing the risk of osteosarcoma. This study aims to investigate the potential association of MDM2 c.346G>A genetic variant with the risk of osteosarcoma in Chinese. A total of 738 subjects were recruited in this study. The genotypes of MDM2 c.346G>A genetic variant were detected by the created restriction site-polymerase chain reaction. Our data suggest that the MDM2 c.346G>A genetic variant is associated with the increased risk of osteosarcoma in the homozygote comparison (AA vs. GG: odds ratio [OR]=2.36, 95% confidence interval [CI] 1.30-4.28, χ2=8.35, p=0.004), recessive model (AA vs.
Ga/gg: OR=2.32, 95% CI 1.30-4.13, χ2=8.50, p=0.004), and allele comparison (A vs. G: OR=1.27, 95% CI 1.01-1.60, χ2=4.34, p=0.037). Results from this study indicated that the allele-A and genotype-AA of MDM2 c.346G>A genetic variant could be an increased risk factor for the susceptibility to osteosarcoma and might be used as a potential molecular marker for evaluating the risk of osteosarcoma.