The nuclear receptor coactivator 5 (NCOA5) was a unique coactivator independent of AF2 that can modulate ERα-mediated transcription. Recent researches have indicated that its downregulation may participate in cancer development and progression. The aims of the present study were to investigate NCOA5 expression in esophageal squamous cell carcinoma (ESCC) and validate its possible influence on patients' prognosis. NCOA5 expression was examined by immunohistochemical staining in 119 ESCC patients' tissues. Ten paired tumor and adjacent normal specimens were examined by Western blot analysis. Statistical analysis was performed to assess its relevance with various clinicopathologic features and its influence on patients' survival. By immunohistochemistry analysis, NCOA5 expression was found to be significantly correlated with differentiation (P = 0.039), T status (P = 0.047) and stage (P = 0.036). Furthermore, we found NCOA5 higher expression in normal tissues than in tumor tissues by Western blot analysis. Univariate analysis showed that poor differentiation (P = 0.035, P = 0.027), lymph node metastasis (P < 0.001, P < 0.001), high T status (P = 0.010, P = 0.012), advanced stage (P < 0.001, P < 0.001) and NCOA5 low expression (P < 0.001, P < 0.001) were significantly correlated with poor prognosis of both disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that NCOA5 low expression (P = 0.019, P = 0.047), high T status (P = 0.015, P = 0.012), lymph node metastasis (P = 0.040, P = 0.021) and advanced stage (P = 0.017, P = 0.046) were independent prognostic factors of poor DFS and OS. Our findings suggest that NCOA5 low expression is associated with ESCC progression and is a potential biomarker in predicting poor prognosis. Further studies of NCOA5 may help develop new therapeutic strategies against ESCC.