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Simple Summary: Pediatric osteosarcoma is one of the most aggressive cancers, and predictions of metastasis and chemotherapy response have a significant impact on pediatric patient survival. Radiogenomics, as methods of analyzing gene expression or image texture features, have previously been used for the diagnosis of chemotherapy responses and metastasis and can reveal the current state of cancer. In this study, we aimed to generate a predictive model using gene expression and 18F-FDG PET/CT image texture features in pediatric osteosarcoma in relation to metastasis and chemotherapy response. A predictive model using radiogenomics technology that incorporates both imaging features and gene expression can accurately predict metastasis and chemotherapy responses to improve patient outcomes. Chemotherapy response and metastasis prediction play important roles in the treatment of pediatric osteosarcoma, which is prone to metastasis and has a high mortality rate. This study aimed to estimate the prediction model using gene expression and image texture features. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) images of 52 pediatric osteosarcoma patients were used to estimate the machine learning algorithm. An appropriate algorithm was selected by estimating the machine learning accuracy. 18F-FDG PET/CT images of 21 patients were selected for prediction model development based on simultaneous KI67 and EZRIN expression. The prediction model for chemotherapy response and metastasis was estimated using area under the curve (AUC) maximum image texture features (AUC_max) and gene expression. The machine learning algorithm with the highest test accuracy in chemotherapy response and metastasis was selected using the random forest algorithm. The chemotherapy response and metastasis test accuracy with image texture features was 0.83 and 0.76, respectively. The highest test accuracy and AUC of chemotherapy response with AUC_max, KI67, and EZRIN were estimated to be 0.85 and 0.89, respectively. The highest test accuracy and AUC of metastasis with AUC_max, KI67, and EZRIN were estimated to be 0.85 and 0.8, respectively. The metastasis prediction accuracy increased by 10% using radiogenomics data. [ABSTRACT FROM AUTHOR]