The aim of this study was to investigate risk factors for esophageal squamous cell carcinoma (ESCC) treated with radiotherapy with or without chemotherapy to guide how to reduce the occurrence of esophageal fistula (EF). 414 patients with ESCC who underwent radiotherapy with or without chemotherapy were collected in Shandong Cancer Hospital from June 2014 to June2018 retrospectively. The clinical characters and dosimetric parameters were recorded. Univariate and multivariate logistic regression analyses were provided to determine the risk factors associated with EF after radiotherapy for ESCC. The cumulative incidences of EF were 11.1% (46/414patient). The median follow-up period was 15.8 months (range: 0.2-82.6months). The median survival time (MST) was 36.8 months for all patients. The MST of patients with EF was 154 days (5.1 months). In univariate analysis, age, T4 stage, N3 stage, TNM clinical stage, sequential chemoradiotherapy, re-radiotherapy, chemotherapy regimens, ulcerative esophageal cancer, esophageal stenosis, the maximum thickness of the tumor and the length of tumor had a correlation with the prevalence of EF. In multivariable logistic regression analysis, age, T4 stage, sequential chemoradiotherapy, re-radiotherapy, chemotherapy regimens, ulcerative esophageal cancer ,esophageal stenosis, the maximum thickness of the tumor were significantly associated with EF. This study found that age, T4 stage, sequential chemoradiotherapy, re-radiotherapy, chemotherapy regimens, ulcerative esophageal cancer, esophageal stenosis, the maximum thickness of the tumor were risk factors clearly associated with EF. Patients with risk factors for EF should be paid close attention. Active treatment should be taken to reduce the occurrence of EF in clinical work.