Centromere protein F (CENP-F), a cell cycle-regulated centromere protein, has been shown to affect numerous tumorigenic processes. This study aimed to clarify the prognostic significance of CENP-F expression in patients with esophageal squamous cell carcinoma (ESCC). The levels of CENP-F messenger RNA and protein were higher in ESCC cell lines than in the normal tissues. An immunohistochemical analysis of paired tissue specimens showed that the CENP-F expression was higher in tumorous tissues than in the adjacent non-tumorous tissues (P < 0.001). Moreover, there was a significant correlation between CENP-F expression and gender (P = 0.012), clinical stage (P = 0.039), and T classification (P = 0.026). Patients with higher CENP-F expression had shorter overall survival than those with lower CENP-F expression (P = 0.009). Multivariate Cox analysis indicated that CENP-F expression is an independent prognostic factor for overall survival (hazard ratio = 0.582, 95% confidence interval = 0.397–0.804, P = 0.041). Importantly, it was found that zoledronic acid (ZOL) could significantly enhance the chemotherapeutic sensitivity of ESCC cell lines with high CENP-F expression to cisplatin, although ZOL alone only exhibited a minor inhibitory effect to ESCC cells. In summary, these findings demonstrate that CENP-F may serve as a valuable molecular marker for predicting the prognosis of ESCC patients. In addition, the data indicate a potential benefit of combining ZOL with cisplatin in ESCC, suggesting that CENP-F expression may have therapeutic implications.