Abstract Background Esophageal fistula is one of the most serious complications of chemotherapy or chemoradiotherapy (CRT) for advanced esophageal cancer. This study aimed to evaluate the performance of quantitative computed tomography (CT) analysis and to establish a practical imaging model for predicting esophageal fistula in esophageal cancer patients treated with chemotherapy or chemoradiotherapy. Methods This study retrospectively enrolled 204 esophageal cancer patients (54 patients with fistula, 150 patients without fistula) and all patients were allocated to the primary and validation cohorts according to the time of inclusion in a 1:1 ratio. Ulcer depth, tumor thickness and length, and minimum and maximum enhanced CT values of esophageal cancer were measured in pretreatment CT imaging. Logistic regression analysis was used to evaluate the associations of CT quantitative measurements with esophageal fistula. Receiver operating characteristic curve (ROC) analysis was also used. Results Logistic regression analysis showed that independent predictors of esophageal fistula included tumor thickness [odds ratio (OR) = 1.167; p = 0.037], the ratio of ulcer depth to adjacent tumor thickness (OR = 164.947; p