Sirtuin-3 (SIRT3) protein is a member of Sirtuins family. It functions as a critical mitochondrial deacetylase, which is involved in a variety of diseases, such as cancer, cardiovascular disease and diabetes. However, its role in esophageal squamous cell carcinoma (ESCC) has never been investigated before. With the help of immunohistochemistry, we studied the clinical significance of SIRT3 expression in ESCC. The receiver operating characteristic method was used to define the SIRT3 IRS cutoff value. The correlations between SIRT3 expression and clinicopathological variables were assessed using Pearson's χ (2) test. To evaluate the clinical significance of SIRT3 expression, Kaplan-Meier analysis was used to compare postoperative survival between different SIRT3 expression groups of ESCC patients. High expression of SIRT3 in ESCC tissues was more frequently observed than corresponding adjacent non-malignant esophageal mucosa tissues. No correlations were found between SIRT3 expression and clinical parameters. Multivariate analysis revealed that SIRT3 expression was an independent prognostic factor in ESCC (HR 1.454, P = 0.034). Increased SIRT3 expression suggests unfavorable prognosis for ESCC patients. Further studies are warranted.