Neoadjuvant treatment has become standard care for patients with resectable esophageal cancer. However, some patients cannot undergo surgery or curative resection because of disease progression during neoadjuvant treatment. The aim of this study is to identify the pretreatment characteristics of patients in whom neoadjuvant treatment failed. The study enrolled 231 patients who underwent chemotherapy with cisplatin and 5-fluorouracil (CF) as neoadjuvant therapy for T1N1-3 or T2-3 any-N esophageal squamous cell carcinoma (ESCC). Of these patients, 201 (87.0%) underwent curative resection (R0) and 30 (13.0%) could not undergo curative resection; 19 patients (8.2%) underwent incomplete resection (R1 or R2), and 11 patients (4.8%) could not undergo surgery because of disease progression. We compared clinical characteristics and survival between patients who underwent curative resection (curative group) and those who could not undergo curative resection (noncurative group) to determine the factors predicting noncurative treatment. The noncurative group had significantly worse disease-specific survival than the curative group (P < 0.001). All patients in the noncurative group had cT3 tumors. In 141 patients with cT3 tumors, those in the noncurative group were more likely to have higher serum SCC antigen concentration (P = 0.021), location of the main tumor in the upper to the middle third of the esophagus (P = 0.071), intramural metastases (P < 0.001), advanced N category (P = 0.016), and bulky lymph node metastases (P = 0.060). Multivariate logistic regression analysis identified location of the main tumor in the upper to the middle third of the esophagus (P = 0.047), intramural metastases (P = 0.002), and nodal metastases (N1, P = 0.014; N2, P = 0.015, respectively) as independent predictors of treatment failure in patients with cT3 tumors. Neoadjuvant CF therapy alone may not be effective for patients with cT3 tumors accompanied by these risk factors, and the efficacy of alternative strategies, such as triplet chemotherapy or chemoradiotherapy, should be evaluated.