Two polymorphisms in the murine double minute 2 (MDM2) gene (rs1690916 and rs2279744) have been associated with the risk of osteosarcoma (OS). When we analyzed these two polymorphisms in two new independents cohorts (Spanish and Slovenian), we found no association. In order to clarify this, we conducted a meta-analysis including six populations, with a total of 246 OS patients and 1,760 controls for rs1690916; and 433 OS patients and 1,959 controls for rs2279744. Pooled odds ratio risks and corresponding 95% CI were estimated to assess the possible associations. Our results showed that these two polymorphisms were not associated with the susceptibility of OS under any genetic model studied. In conclusion, the present meta-analysis indicates that MDM2 rs1690916 and rs2279744 cannot be considered as genetic risk factors for OS susceptibility in the different populations. Therefore, the influence of these two polymorphisms on the risk of OS may be less important than previously suggested. Future studies are needed to confirm these results.