Objective To test the hypothesis that portomesenteric venous resection (PVR) following neoadjuvant chemotherapy (NAC) is technically safe and yields superior oncologic outcomes compared to upfront surgery, despite the selection of patients with more aggressive baseline disease biology. Methods A propensity score-matched analysis was performed on 214 patients undergoing pancreatoduodenectomy with PVR for borderline resectable pancreatic adenocarcinoma (2003–2022). Patients were stratified into NAC (n=113) and upfront surgery (n=101) cohorts. Perioperative safety, histopathological response, and survival outcomes were compared. Results Matching yielded 97 patients per group. The NAC cohort presented with significantly higher baseline tumor burden (median CA19-9 430 vs 145 U/mL; p<0.001). Despite this biological disadvantage, NAC was associated with superior R0 resection rates (61.9% vs 31%, p<0.001) and reduced intraoperative blood loss (p=0.004). Crucially, NAC significantly altered the pattern of venous involvement: neoadjuvant patients exhibited less deep venous invasion (intima/lumen) compared to the upfront group (p=0.03), with venous involvement more frequently confined to the adventitia. Short-term morbidity and mortality were equivalent. NAC significantly improved overall survival at 1, 3, and 5 years (85.6%, 38.1%, 24.4% vs 69.1%, 28.0%, 18.6%; all p<0.05). Conclusion PVR following NAC is technically safe and associated with improved survival compared to upfront surgery. This survival benefit is achieved despite higher baseline biological tumor burden in the neoadjuvant cohort, confirming that NAC effectively downstages high-risk disease to allow for successful curative-intent vascular resection.