Abstract: Objective To investigate the relationship between cortactin (CTTN) expression and radiosensitivity in esophageal squamous cell carcinoma (ESCC). Methods Clinical data were collected from 80 patients who were diagnosed with ESCC by electronic gastroscopy and pathology at Huai'an Hospital Affiliated to Xuzhou Medical University between January 2020 and December 2023. The expression of CTTN in gastroscopic biopsy specimens was detected by immunohistochemistry (IHC). The relationship between CTTN expression levels, clinical data, and short-term radiotherapy efficacy was analyzed. Western blotting (WB) and quantitative real-time PCR (qRT-PCR) were used to detect CTTN expression in human ESCC cell lines KYSE450 (K450), KYSE150 (K150), and their radioresistant sublines KYSE450R (K450R) and KYSE150R (K150R). Results Among the patients, 42 were classified as radiosensitive and 38 as radioresistant. Significant differences were observed between the two groups in clinical stage, N stage, and whether concurrent chemoradiotherapy was performed (P<0.05). CTTN expression was significantly correlated with N stage (P<0.05) but not with concurrent chemoradiotherapy (P>0.05). The expression level of CTTN in the radiosensitive group was higher than that in the radioresistant group (P<0.05). Logistic regression analysis indicated that CTTN expression and concurrent chemoradiotherapy were influencing factors for ESCC radiosensitivity (P<0.05). WB and qRT-PCR results showed that CTTN expression in K450R and K150R cells was lower than in K450 and K150 cells (P<0.05). Conclusions The radiosensitivity of ESCC may be associated with CTTN expression levels. Patients with higher CTTN expression demonstrates better short-term efficacy following radiotherapy. These findings suggest that CTTN may serve as a potential predictive biomarker for radiosensitivity in ESCC patients.