Background: Neoadjuvant chemotherapy with docetaxel, cisplatin plus 5-FU (Neo DCF) is one of the standard treatments for locally advanced esophageal squamous cell carcinoma (ESCC) in Japan based on the results of the JCOG1109 NExT study. As Neo DCF is both highly effective and high rate of adverse events, it is important to confirm clinical outcomes in the clinical practice and to explore clinical factors that predict treatment efficacy and adverse events (AEs) for treatment optimization. Methods: ESCC patients who were treated with Neo DCF between July 2016 and May 2023, were enrolled. Three courses of DCF (DTX [day 1]: 70 mg/m2, CDDP [day 1]: 70 mg/m2, 5-FU [continuous infusion on days 1-5]: 750 mg/m2, every 3 weeks) were planned, and prophylactic antibiotics was administered on days 5-15. We retrospectively assessed disease free survival (DFS), pathological response, AEs. Pathological response was assessed according to the Becker’s Criteria. Subgroup analyses of clinical factors related to the pathological response and AEs were also performed. Results: In total, 91 patients (median age, 62.3 years) were enrolled. Clinical stages of this cohort were 8.8% (I),16.4% (II), 69.2% (III), and 5.5% (IVA), respectively. After Neo DCF treatment, 90 patients (98.9%) underwent curative surgery. Median DFS and 3-year DFS rate were not reached and 76.9%. The incidence of pathological complete response (pCR) and major pathological response (MPR) were 11.1% (10/90) and 35.6% (32/90), respectively. There were no cases of recurrence in patients with pCR and MPR. The most common grade 3 or 4 AEs were neutropenia (58/91, 63.7 %), diarrhea (15/91, 16.5%), and thrombosis (9/91, 9.9%), respectively. Febrile neutropenia occurred in 33 patient (36.2%). Clinical T stage was significantly associated with pCR (P = 0.033). Conclusions: Neo DCF was effective and tolerable in the real-world ESCC patients in Japan.