Purpose <p>To evaluate the predictive performance of a clinical-CT-radiomics nomogram based on radiomics signature and independent clinical-CT predictors for predicting endoscopic red color sign (RC) in cirrhotic patients with esophageal varices (EV).</p> Methods <p>We retrospectively evaluated 215 cirrhotic patients. Among them, 108 and 107 cases were positive and negative for endoscopic RC, respectively. Patients were assigned to a training cohort (n = 150) and a validation cohort (n = 65) at a 7:3 ratio. In the training cohort, univariate and multivariate logistic regression analyses were performed on clinical and CT features to develop a clinical-CT model. Radiomic features were extracted from portal venous phase CT images to generate a Radiomic score (Rad-score) and to construct five machine learning models. A combined model was built using clinical-CT predictors and Rad-score through logistic regression. The performance of different models was evaluated using the receiver operating characteristic (ROC) curves and the area under the curve (AUC).</p> Results <p>The spleen-to-platelet ratio, liver volume, splenic vein diameter, and superior mesenteric vein diameter were independent predictors. Six radiomics features were selected to construct five machine learning models. The adaptive boosting model showed excellent predictive performance, achieving an AUC of 0.964 in the validation cohort, while the combined model achieved the highest predictive accuracy with an AUC of 0.985 in the validation cohort.</p> Conclusion <p>The clinical-CT-radiomics nomogram demonstrates high predictive accuracy for endoscopic RC in cirrhotic patients with EV, which provides a novel tool for non-invasive prediction of esophageal varices bleeding.</p> Graphical Abstract <p></p>