Background: Definitive chemoradiotherapy (CRT) is a reasonable approach for patients with locally advanced esophageal cancer who are not surgical candidates. This study was performed to investigate whether endosonography (EUS) assessment of tumor area response is a useful prognostic marker in patients with squamous cell carcinoma (SCC) of the esophagus who receive definitive CRT. Methods: A total of 33 patients who received definitive CRT for locally advanced esophageal SCC were enrolled. The maximal transverse cross-sectional area of the tumor was measured before and after definitive therapy. EUS response was defined as a ≥50% reduction of the tumor area after definitive CRT. Results: Based on EUS evaluation, there were 20 nonresponders (60.6%) and 13 responders (39.4%). The median progression-free survival (PFS) was significantly longer in EUS responders than EUS nonresponders (p = 0.005). However, there was no statistical significance in overall survival according to EUS response (p = 0.120). During multivariate analysis, EUS response to definitive CRT was the only significant factor associated with PFS (p = 0.045), whereas EUS response to definitive CRT was not associated with overall survival (p = 0.221). Conclusions: A reduction of the maximal cross-sectional tumor area measured by EUS correlates with a superior prognosis in patients with locally advanced SCC of the esophagus after definitive CRT.