Purpose: We aimed to test whether -internexin could be a molecular biomarker of tumor aggressiveness and prognosis in pancreatic neuroendocrine tumors (PNETs). Patients and Methods: Using immunohistochemical staining and Western blot, we detected the expression of α-internexin in 350 tumors from 343 patients, of whom 257 were followed up. Methylation ofα-internexin promoter was examined by bisulfite sequencing to identify the crucial region that determines gene expression. Methylation of gene promoter in tumors was quantitatively measured by denaturing high performance liquid chromatography (DHPLC). We correlated -internexin expression with clinicopathological characteristics. Results: α-Internexin was expressed in 53% of 350 PNETs. The reduced expression of α-internexin wassignificantly associated with advanced stage (P<.0001), metastases (P<.0001),andrecurrence (P = .003). -Internexin expression was found in 57.1% of 212 surviving patients and in 17.1% of 35 deceased patients (P < .0001). Reduced expression of α-internexin was associated with shorter overall survival in PNET patients (log rank P<.0001) as well as in patients with noninsulinoma and nonfunctional (NF)-PNETs (log rank P = 0.0073 and P = 0.010, respectively). The crucial region of -internexin promoter (-149 to+96 nucleotides [nt]) was identified, and the hypomethylation of this area in PNETs was significantly associated with gene expression (P = .015). Conclusion: -Internexin can be a useful prognostic biomarker for PNETs. © 2014 by the Endocrine Society.