Protein tyrosine phosphatase 4A2 (PTP4A2) has been implicated as an oncogenic protein in several human cancers. However, the level of PTP4A2 expression and its prognostic significance in nasopharyngeal carcinoma (NPC) remains unknown. In this study, Western blotting (WB), quantitative realtime PCR (qT-PCR) and immunohischemistry (IHC) was applied to evaluated the expression levels of PTP4A2 in NPC cell lines and tumor tissues combining two independent cohorts. Receiver-operator curve (ROC) analysis was used to assessed the optimal cut-off score in training cohort (266 cases). This cutoff score was subjected to determine the association of PTP4A2 expression with patients' clinical characteristics and survival outcome in the validation cohort (201 cases) and the overall population (467 cases). We found that PTP4A2 were significantly overexpressed in NPC cell lines compared with normal nasopharyngeal epithelial cell. Moreover, overexpression of PTP4A2 was positively correlated with advanced T classification (P< 0.001) and TNM stages (P< 0.001). And higher PTP4A2 expression was an independent prognostic factor for adverse overall survival (P< 0.05) and poor disease-free survival (P< 0.05). Our results demonstrated that the overexpression of PTP4A2 was closely associated with poor survival outcome in patients with NPC and may represent a novel prognostic biomarker and therapeutic target for this disease.