Tyrosine-protein phosphatase nonreceptor type 12 (PTPN12) has been proposed to predict prognosis of various human cancers. However, the clinicopathologic and prognostic significance of PTPN12 expression in NPC has not yet been elucidated. The objective of this study was to investigate the clinicopathological and prognostic implication of PTPN12 in nasopharyngeal carcinoma (NPC) patients. Protein expression levels of PTPN12 were explored by semiquantitative immunohistochemical staining on archival formalin-fixed, paraffin-embedded pathological specimens consisting of 203 NPCs, and 40 normal nasopharyngeal mucosa tissues. Receiver operating characteristic (ROC) curve analysis was employed to determine the cutoff score of PTPN12 expression in NPCs. The PTPN12 immunohistochemical staining results were then correlated with various clinicopathological features and patients' prognosis using various statistical models. Our results showed that decreased expression of PTPN12 was more frequently observed in NPC tissues compared with the normal nasopharyngeal mucosa. Further correlation analyses indicated that the decreased expression of PTPN12 was significantly associated with tumor T classification, N classification, distant metastasis, and clinical stage in NPCs (P < 0.05). Univariate analysis showed a significant association between the decreased expression of PTPN12 and adverse overall survival and disease-free survival (P < 0.05). More importantly, multivariate analysis identified the PTPN12 expression in NPC as an independent prognostic factor. The decrease expression of PTPN12 might be important in conferring a more aggressive behavior in NPC. Thus, PTPN12 expression may be used as a novel independent prognostic biomarker for patients with NPC.