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The study aimed to investigate the clinical significance of interim response evaluation during definitive chemoradiotherapy (dCRT) in predicting overall treatment response and survival of patients with locally advanced esophageal squamous cell carcinoma (LAESCC). We reviewed 194 consecutive patients treated with dCRT for biopsy-confirmed LAESCC. A total of 51 patients met the inclusion criteria. Interim response was assessed by defining a region of interest in initial and adaptive computed tomography (CT) images and subsequently examined against the overall treatment response assessed three months after dCRT, treatment failure pattern, overall survival (OS), and progression-free survival (PFS) estimates. Reductions in both the area and maximal diameter of the primary lesion (p &lt, 0.001, p &lt, 0.001, respectively) and those of the metastatic lymph nodes (LN) (p = 0.002, 0.001, respectively) in interim analysis were significantly higher among patients who achieved complete response (CR) than among those who did not. OS was significantly longer among patients who showed ≥30% interim reduction in the area and maximal diameter of the primary lesion and among those who showed such reduction in both the primary lesion and LN. PFS was significantly longer in the patients with ≥30% interim reduction in the area of the primary lesion. In addition, the proportion of cases with locoregional failure began decreasing at interim response of 20% or higher, while the proportion of cases with outfield failure followed the opposite pattern, increasing at interim response of 20% or higher. Among patients treated with dCRT for LAESCC, interim response assessed using adaptive CT images correlated with overall CR and OS rates. The evaluation of tumor burden reduction during dCRT may help predict patient prognosis.