ObjectiveTo predict postoperative anastomotic leakage (AL) following radical resection of esophageal squamous cell carcinoma (ESCC) based on clinical data and preoperative enhanced Computed tomography(CT) radiomics of the esophagus.MethodWe retrospectively analyzed the clinicopathological and radiological data of 213 patients with ESCC who received radical resection at Xiangyang No.1 People’s Hospital from July 2011 to February 2024. 3D slicer software was used in combination with Lasso extraction and 10-fold cross-validation to extract texture parameters from contrast-enhanced CT images and generate Delta-Radscores. Several models were built using logistic regression to predict postoperative AL in ESCC.ResultsIn the training set, the univariate analysis confirmed that duration of surgery, surgical method, delta radscore 1, delta radscore 2, contrast enhancement patterns, peripheral lymph node metastasis, post thoracotomy pulmonary infection(PTPI), and hot pot were risk factors for ESCC-AL (P<0.05 for both). The multivariate analysis showed that delta radscore 1, delta radscore 2, PTPI, and hot pot were independent risk factors for AL (P<0.05 for all). These results were verified by the XGboost machine learning model. The combinational model based on all of the above risk factors [AUC 0.900, OR 0.0282, 95%CI 0.841-0.943] outperformed either the clinical model[AUC 0.759, OR 0.0392, 95%0.683-0.825,P<0.05] or the imaging model[AUC 0.869, OR 0.0335, 95%0.804-0.918,P=0.1277] alone in predictive efficacy. The decision curve proved that the combinational model had a higher clinical net benefit. The nomogram generated via the combinational model simplified the predictive process. The same predictions were verified in the testing set.ConclusionDelta radscore 1, delta radscore 2, PTPI, and hot pot were related to ESCC-AL. The novel nomogram created using enhanced CT radiomics informed perioperative management and improved the survival quality of ESCC patients.