JWA is involved in the regulation of many cellular processes. Recent studies have indicated a potential role for altered JWA expression and function in tumor development and progression. The purpose of this study was to investigate the expression and prognostic significance of JWA in human esophageal squamous cell carcinoma (ESCC). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot assays were performed to detect the expression of JWA mRNA or protein in paired sample tissues from 20 ESCC patients. Expression levels of JWA protein in archival 292 formalin-fixed, paraffin-embedded specimens were also analyzed by immunohistochemistry. Finally, the correlation between JWA expression, clinicopathological factors, and patient survival was evaluated. RT-qPCR results showed that the levels of JWA mRNA were significantly lower in tumor tissue specimens than in the matched nontumor tissues. This finding was supported by Western blot analysis. Immunohistochemical staining data indicated that JWA protein level was correlated closely with the tumor cell differentiation, tumor invasion, lymph node metastasis, and distant metastasis. Kaplan-Meier survival analysis showed that low expression level of JWA resulted in a significantly poor prognosis of ESCC patients. Cox regression analysis revealed that the JWA expression level was an independent prognostic parameter for the overall survival rate of ESCC patients. In conclusion, our data suggest that JWA plays an important role in the occurrence and progress of human ESCC and that high expression level of JWA may predict a favorable prognosis in ESCC patients.