Protein tyrosine phosphatase receptor type S is a tumor suppressor gene, located at chromosome 19p13.3, frequently inactivated through deletions or epigenetic mechanisms in many types of cancers. In this study, we investigate protein tyrosine phosphatase receptor S (PTPRS) expression level, clinicopathological and prognostic significance in 205 cases of esophageal squamous cell carcinoma (ESCC). Paraffin embedded tissue with immunohistochemistry methods was adopted to exam PTPRS expression in ESCC and paired normal esophageal mucosa tissues on Tissue Microarrays (TMAs). The protein tyrosine phosphatase receptor S was significantly down-regulated in ESCC (58.0%) relative to normal tissues (43.9%) (P=0.006). Statistical analysis revealed that reduced PTPRS expression was significantly associated with TNM stage (P=0.013), invasion depth (P<0.001), local lymph node metastasis (P=0.042) and tumor differentiation (P=0.001). Furthermore, Kaplan-Meier survival analysis revealed that low expression of PTPRS significantly correlated with poor survival of ESCC patients (P=0.002). Cox regression analysis confirmed PTPRS expression as an independent predictor of the overall survival of ESCC patients (HR=1.573, P=0.049). The 5-year overall survival rates in patients with high and low PTPRS expression were 50.6% and 37.2%, respectively. PTPRS deficiency is independently associated with shorter survival and increased recurrence in patients. Our data offer convincing evidence that loss of PTPRS expression may predict an aggressive clinical course in ESCC patients. PTPRS may function as a tumor suppressor and play an important role in ESCC growth and metastasis.