BackgroundRegional lymph node metastasis is a contributor for poor prognosis in osteosarcoma. However, studies on risk factors for predicting regional lymph node metastasis in osteosarcoma are scarce. This study aimed to develop and validate a model based on machine learning (ML) algorithms.MethodsA total of 1201 patients, with 1094 cases from the surveillance epidemiology and end results (SEER) (the training set) and 107 cases (the external validation set) admitted from four medical centers in China, was included in this study. Independent risk factors for the risk of lymph node metastasis were screened by the multifactorial logistic regression models. Six ML algorithms, including the logistic regression (LR), the gradient boosting machine (GBM), the extreme gradient boosting (XGBoost), the random forest (RF), the decision tree (DT), and the multilayer perceptron (MLP), were used to evaluate the risk of lymph node metastasis. The prediction model was developed based on the bestpredictive performance of ML algorithm and the performance of the model was evaluatedby the area under curve (AUC), prediction accuracy, sensitivity and specificity. A homemade online calculator was capable of estimating the probability of lymph node metastasis in individuals.ResultsOf all included patients, 9.41% (113/1201) patients developed regional lymph node metastasis. ML prediction models were developed based on nine variables: age, tumor (T) stage, metastasis (M) stage, laterality, surgery, radiation, chemotherapy, bone metastases, and lung metastases. In multivariate logistic regression analysis, T and M stage, surgery, and chemotherapy were significantly associated with lymph node metastasis. In the six ML algorithms, XGB had the highest AUC (0.882) and was utilized to develop as prediction model. A homemade online calculator was capable of estimating the probability of CLNM in individuals.ConclusionsT and M stage, surgery and Chemotherapy are independent risk factors for predicting lymph node metastasis among osteosarcoma patients. XGB algorithm has the best predictive performance, and the online risk calculator can help clinicians to identify the risk probability of lymph node metastasis among osteosarcoma patients.