Background: Microvascular invasion (MVI) has been proved to be poor prognostic factor in many cancers. To date, only one study published highlights the relationship between this factor and the natural history of pancreatic cancer. The aim of this study was to assess the impact of MVI, on disease-free survival (DFS) and overall survival (OS), after pancreatico-duodenectomy (PD) for pancreatic head adenocarcinoma. Secondarily, we aim to demonstrate that MVI is the most important factor to predict OS after surgery compared with resection margin (RM) and lymph node (LN) status. Materials and methods: Between January 2015 and December 2017, 158 PD were performed in two hepato-bilio-pancreatic (HBP) centers. Among these, only 79 patients fulfilled the inclusion criteria of the study. Clinical-pathological data and outcomes were retrospectively analyzed from a prospectively maintained database. Results: Of the 79 patients in the cohort, MVI was identified in 35 (44.3%). In univariate analysis, MVI (P = .012 and P < .0001), RM (P = .023 and P = .021), and LN status (P < .0001 and P = .0001) were significantly associated with DFS and OS. A less than 1 mm margin clearance did not influence relapse (P = .72) or long-term survival (P = .48). LN ratio > 0.226 had a negative impact on OS (P = .044). In multivariate analysis, MVI and RM persisted as independent prognostic factors of DFS (P = .0075 and P = .0098, respectively) and OS (P < .0001 and P = .0194, respectively). Using the likelihood ratio test, MVI was identified as the best fit to predict OS after PD for ductal adenocarcinomas compared with the margin status model (R0 vs R1) (P = .0014). Conclusion: The MVI represents another major prognostic factor determining long-term outcomes.