Objective: To establish a CT image radiomics-based prediction model for the differential diagnosis of silicosis and tuberculosis nodules. Methods: A total of 53 patients with silicosis and 89 patients with tuberculosis who underwent routine CT scans in Suzhou Fifth People's Hospital from January to August, 2018 were enrolled in this study. AK/ITK software was used to segment the images to obtain 139 silicosis lesions and 119 tuberculosis lesions. For each lesion image, 396 features were extracted, and feature dimension reduction was applied to select the most characteristic feature subset. Support vector machine (SVM) , feedforward back propagation neural network (FNN-BP) , and random forest (RF) were implemented using R software (Rstudio V1.1.463) , and the algorithm that achieved the largest area under of the receiver operating characteristic (ROC) curve (AUC) was selected as the final prediction model. Results: RF was the best prediction model for the differential diagnosis of silicosis and tuberculosis nodules, with an accuracy of 83.1%, a sensitivity of 0.76, a specificity of 0.9, and an AUC of 0.917 (95% confidence interval: 0.8431-0.9758) . RF had a significantly larger AUC than SVM and FNN-BP (P<0.05) . Conclusion CT image-based RF prediction model can be used to differentially diagnose silicosis and tuberculosis nodules.