Background: We aimed to evaluate the expression and prognostic significance of N-myc downstream-regulated gen-1 (NDRG-1), O⁶-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) by immunohistochemistry (IHC) and methylation analysis in resected pancreatic neuroendocrine tumors (PanNET). Methods: Ninety-two patients with resected primary PanNET and follow-up > 24 months were included in this study. Nuclear staining for MGMT and PHLDA-3 were scored as 0, 1-5%, 6-50% and ≥ 51%; cytoplasmic NDRG-1 staining was scored based on intensity and pattern from 0 to 2. We then grouped IHC scores for MGMT (absent versus any expression); for NDRG-1 (0 versus 1 versus 2) and for PHLDA-3 ( < 50% versus ≥ 51%). Finally, we developed an immunohistochemistry prognostic score (IPS) based on MGMT, NDRG-1 and PHLDA-3 IHC expression to predict disease free survival (DFS) and overall survival (OS). The discriminatory ability of multivariate models combining the IPS and important clinical variables was assessed with Harrel’s c-index (HCI) and a modification of Harrell’s c-index (mHCI). Results: DFS was significantly worse in patients without any expression of MGMT compared with those with any grade of expression (HR: 2.21; 95%CI: 0.97-5.02; p = 0.013), in patients with moderate or high score for NDRG-1 (p = 0.005), and in those with high-expression for PHLDA-3 (HR: 1.94; 95%CI: 1.05,3.6; p = 0.036). A significant difference in OS was observed based on NDRG-1 score (p = 0.013). In multivariate analyses, ki-67 (HR: 2.45; 95% CI: 1.20-5.01; p = 0.01) and IPS (HR: 2.68; 95% CI: 1.60,4.49; p = 0.00018) were independent prognostic factors for DFS, while age (HR: 7.67; 95% CI: 2.14,27.45; p = 0.0017) and IPS (HR: 2.67; 95% CI: 1.11, 6.41; p = 0.03) were independent prognostic factors for OS. HCI for the multivariate DFS and OS models were 0.796 and 0.788, respectively. Conclusions: Our IPS is a useful prognostic biomarker for recurrence and survival in patients following resection for PanNET. Prospective studies are warranted to validate our findings and determine its role for patients’ selection to neo/adjuvant treatments