The goal of this study was to discover clinical factors linked to overall survival in patients with high-grade osteosarcoma who had received neoadjuvant therapy and to develop a prognostic nomogram and risk classification system.A total of 762 patients with high-grade osteosarcoma were included in this study. In the training cohort, Cox regression analysis models were used to find prognostic variables that were independently linked with overall survival. To predict overall survival at 3, 5, and 8 years, a nomogram is created. In addition, in both the internal and external validation cohorts, receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA) were utilized to assess the prediction model's performance.The age, size of the tumor, and the stage of the disease are all important predictive variables for overall survival. The training and validation cohorts have C-indexes of 0.699 and 0.669, respectively. At the same time, the area under the curve values for both cohorts also showed that the nomogram had good discriminatory power. The calibration curve demonstrated the good performance and predictive accuracy of the model. The DCA results suggest that the nomogram has a wide range of therapeutic applications. Furthermore, a new risk classification system based on the nomogram was established, which allows all patients to be classified into three subgroups as high, middle, and low risk of death.The prognostic nomogram constructed in this study may provide a better precise prognostic prediction for patients with high-grade osteosarcoma after neoadjuvant chemotherapy.Copyright © 2022 Zhangheng Huang et al.