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Neoadjuvant chemotherapy (NAC) significantly extends survival in advanced esophageal squamous cell carcinoma (ESCC), but the short-term outcomes for cT4 ESCC remain controversial. Many NAC regimens have been previously reported, although no study has reported a regimen of irinotecan and nedaplatin for cT4 potential resectable ESCC. We evaluated the short-term outcomes of NAC with irinotecan and nedaplatin in a single cycle followed by esophagectomy on cT4 resectable ESCC. A total of 51 patients with cT4 potentially resectable ESCC were eligible for this study. Twenty of these patients underwent NAC, and the other 31 patients underwent surgery alone. The toxicities and response of NAC were evaluated. The clinicopathologic characteristics, responses, toxicities, surgical outcomes, postoperative complications, and survival time between the two groups were analyzed. No significant differences were found in clinicopathologic characteristics between the groups (P  > 0.05). The response rate of NAC was 75% (15/20). The differences in the long-axis diameter of the tumor and cT stage between pre- and post-NAC were significant (P  < 0.05). Twenty-four toxic events occurred in 11 patients of the NAC group, and 20/24 of these were mild. The R0 resection rates in the NAC group and the surgery alone group were 85% and 64.5%, with no statistically significant difference (P  > 0.05). Differences in the pathological T stage and pathological tumor-node-metastasis (TNM) stage were significant (P  < 0.05). The overall survival (OS) time and mortality in the NAC group versus the surgery alone group were 31.57 ± 3.06 months versus 15.24 ± 1.46 months and 25% versus 61.3%, respectively. The differences in OS and mortality were significant (P  < 0.05). The NAC group and R0 resection were significant and independent predictors of positive prognosis. NAC with irinotecan and nedaplatin in a single cycle followed by esophagectomy on cT4 resectable ESCC as a new NAC is safe and effective. [ABSTRACT FROM AUTHOR]