Objective: According to the current treatment protocol of the Cooperative Osteosarcoma Study, it is mandatory to determine the histological response to neoadjuvant chemotherapy treatment before surgical removal of the tumor, particularly if a limb salvage procedure is planned. The aim of this systematic, retrospective study was to evaluate the ability of 2-(18F) fluoro-2-deoxy-D-glucose positron-emission tomography/computed tomography to predict chemotherapy response of osteosarcoma and to identify a simple promising method for noninvasive evaluation of neoadjuvant chemotherapy response in osteosarcoma. Methods: The PubMed database was searched to identify and analyze relevant published reports. In particular, correlations between tumor-to-background ratio (TBR), standard uptake value (SUV) and histological response to chemotherapy were assessed. Results: It was found that good responses are achieved in patients with TBR after chemotherapy (TBR2)/TBR before chemotherapy (TBR1) < 0.470 (positive predictive value [PPV] = 92.31%, negative predictive value [NPV] = 82.76%, sensitivity [S] = 87.80%, specificity [SP] = 88.89%), whereas poor responses occur in patients with SUV after chemotherapy/before chemotherapy (SUV2/SUV1) > 0.396 (PPV = 73.68%, NPV = 73.33%, S = 63.64%, SP = 81.48%). Conclusion: Changes in TBR are better predictors of chemotherapy response than SUV in osteosarcoma patients. Therefore, we believe that choice of surgical strategy is optimally based on changes in TBR.