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Background: To develop and validate a survival model with clinico-biological features and 18F- FDG PET/CT radiomic features via machine learning, and for predicting the prognosis from the primary tumor of colorectal cancer.Methods: A total of 196 pathologically confirmed patients with colorectal cancer (stage I to stage IV) were included. Preoperative clinical factors, serum tumor markers, and PET/CT radiomic features were included for the recurrence-free survival analysis. For the modeling and validation, patients were randomly divided into the training (n = 137) and validation (n = 59) set, while the 78 stage III patients [training (n = 55), and validation (n = 23)] was divided for the further experiment. After selecting features by the log-rank test and variable-hunting methods, random survival forest (RSF) models were built on the training set to analyze the prognostic value of selected features. The performance of models was measured by C-index and was tested on the validation set with bootstrapping. Feature importance and the Pearson correlation were also analyzed.Results: Radiomics signature (containing four PET/CT features and four clinical factors) achieved the best result for prognostic prediction of 196 patients (C-index 0.780, 95% CI 0.634-0.877). Moreover, four features (including two clinical features and two radiomics features) were selected for prognostic prediction of the 78 stage III patients (C-index was 0.820, 95% CI 0.676-0.900). K-M curves of both models significantly stratified low-risk and high-risk groups (P < 0.0001). Pearson correlation analysis demonstrated that selected radiomics features were correlated with tumor metabolic factors, such as SUVmean, SUVmax.Conclusion: This study presents integrated clinico-biological-radiological models that can accurately predict the prognosis in colorectal cancer using the preoperative 18F-FDG PET/CT radiomics in colorectal cancer. It is of potential value in assisting the management and decision making for precision treatment in colorectal cancer. Trial registration The retrospectively registered study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (No. 1909207-14-1910) and the data were analyzed anonymously. [ABSTRACT FROM AUTHOR]