Background <p>Neutrophil extracellular traps (NETs) have been implicated in cancer progression by enhancing cancer cell motility through the coiled-coil domain-containing protein 25 (CCDC25).</p> Objective <p>This study aimed to evaluate the prognostic value of CCDC25 expression in patients with esophageal squamous cell carcinoma (ESCC).</p> Method <p>Tissue specimens from patients who underwent radical esophagectomy for ESCC were analyzed to investigate the relationship between CCDC25 expression, clinicopathological features, and prognosis. Western blotting was conducted to compare CCDC25 expression in tumor and non-tumorous tissues (<i>n</i> = 4). Immunohistochemical staining was performed to categorize patients into two groups based on CCDC25 expression: CCDC25^high (<i>n</i> = 80) and CCDC25^low (<i>n</i> = 40).</p> Results <p>CCDC25 expression was significantly higher in tumor tissues compared with non-tumorous tissues (<i>p</i> = 0.006). Patients in the CCDC25^high group had a higher likelihood of poorly differentiated tumors; however, no significant differences were observed in the other clinicopathological features between the two groups. High CCDC25 expression was associated with significantly lower relapse-free survival (RFS) rate (<i>p</i> = 0.03) but not overall survival (OS) [<i>p</i> = 0.07]. Multivariate analysis revealed that high CCDC25 expression and tumor depth were independent predictors of both RFS and OS. Furthermore, high CCDC25 expression was significantly associated with worse prognosis in patients with high postoperative neutrophil counts (≥ 9600/µL) and those with postoperative infectious complications.</p> Conclusions <p>High expression of CCDC25 was identified as an unfavorable prognostic factor in patients with ESCC, particularly in those with elevated postoperative neutrophil counts. Targeting CCDC25 could potentially improve prognosis in specific subgroups of patients with ESCC.</p>