Our previous study showed that knockdown of high-mobility group A2 (HMGA2) could suppress nasopharyngeal carcinoma (NPC) cell migration, invasion, and epithelial-mesenchymal transition (EMT) process, and HMGA2 is a direct functional target of let-7 to regulate NPC cell migration, invasion, and EMT process. However, little is known about the clinical and prognostic significance of HMGA2 protein in NPC patients. The purpose of this study is to identify the clinical and prognostic roles of HMGA2 in NPC patients. We initially analyzed the microarray data and verified mRNA and protein levels of HMGA2 in NPC tissues. Immunohistochemical staining for HMGA2 protein was performed in 116 NPC patients. The associations between HMGA2 protein expression and clinicopathologic features and its prognostic significance were analyzed. In our results, we found mRNA and protein expressions of HMGA2 were upregulated in NPC tissues and cell lines. In 116 NPC tissue samples, we observed that HMGA2 protein overexpression was associated with clinical stage, lymph node metastasis, and distant metastasis. Moreover, NPC patients with high levels of HMGA2 protein expression had shorter overall survival in comparison to patients with low levels of HMGA2 protein. In multivariate analysis, HMGA2 protein overexpression was an unfavorable prognostic factor for NPC patients. In conclusion, HMGA2 is an important biomarker to predicting NPC patient's survival time.