Background: The standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is platinum-based definitive chemoradiotherapy (dCRT). Previous clinical trials have indicated a clinical complete response (cCR) rate of 11%-25% and median overall survival (OS) of 9-10 months. The cCR rate is strongly correlated with good prognosis, however the predictive factors have not been elucidated. Methods: In this multi-institutional retrospective study, we evaluated the efficacy and safety of dCRT in patients with unresectable locally advanced ESCC. “Unresectable” was defined as the primary lesion (T4b) invading adjacent structures such as the aorta, vertebral body, and trachea, or the regional and/or supraclavicular lymph nodes (LNT4b) invading unresectable adjacent structures. cCR was determined by both computed tomography and endoscopy based on the Response Evaluation Criteria in Solid Tumors (version 1.1) with modifications and Japanese Classification of Esophageal Cancer (11th edition), respectively. Results: A total of 175 patients who started dCRT between January 2013 to March 2020, were included in this study. The overall median age was 68 (31-86). A total of 95 (54%) patients had a performance status of 0. Of these, 124 (71%) patients had T4b and 81 (46%) had LNT4b. The clinically involved site were as follows: thoracic aorta (22%), tracheobronchial tree (73%), and others (14%). The median tumor length was 6 (2-22) cm. 56 (32%) patients were tube-fed owing to obstructive tumors. 165 (96%) patients completed at least one cycle of chemotherapy with 60 Gy of radiation. Further, 84 (48%) patients received consolidation chemotherapy following dCRT. The confirmed cCR rate was 24% (42/175). At a median follow-up interval of 20 months, the 2-year OS and progression-free survival (PFS) rates of cCR cases vs. non-cCR cases were 90% vs. 31% (log-rank p < 0.001) and 59% vs. 2% (log-rank p < 0.001), respectively. Multivariate analysis of the clinicopathological factors contributing to cCR revealed that a tumor length of≥6 cm (OR, 0.4; 95% CI, 0.2–0.9 p = 0.03) was the only a significant predictive factor. The primary adverse events of grade 3 or above were esophagitis (32%), pneumonitis (13%), fistula formation (10%), febrile neutropenia (9%), and dyspnea (6%). Among 22 patients who originally presented with fistula formation, fistula disappeared in 14 (64%), including 3 cCR cases. Two (1%) sudden deaths secondary to severe hemorrhage and suspected aortic fistula were observed during the treatment period. Conclusions: dCRT is feasible for patients with unresectable locally advanced ESCC. The cCR rate of dCRT is consistent with that reported in previous clinical trials, and favorable OS and PFS rates were observed in patients with cCR. Tumor length was observed to be a significant predictive factor of cCR. Research Sponsor: None.