Not all patients with radiologically defined borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) require portomesenteric venous resection (PVR). This study evaluates the impact of neoadjuvant chemotherapy (NAC) specifically within the high-risk cohort of patients requiring definitive PVR during pancreatoduodenectomy. Methods A retrospective propensity score–matched (PSM) analysis was performed on 214 patients undergoing pancreatoduodenectomy with PVR for BR-PDAC (2003–2022). Matching yielded 97 patients per cohort (NAC vs. upfront surgery). Outcomes included perioperative safety, depth of venous wall invasion, and survival. Results Following PSM, NAC was associated with significantly lower estimated blood loss (500 mL vs 670 mL, p=0.004) despite requiring significantly longer venous resection segments (30 mm vs 20 mm, p=0.04). Pathologically, NAC resulted in higher R0 resection rates (61.9% vs 32.0%, p<0.001) and significantly reduced depth of venous invasion, with less frequent intimal involvement (10.3% vs 22.7%, p=0.03). However, no statistically significant difference was observed in overall survival (HR 0.78, 95% CI 0.57–1.06) or disease-free survival (HR 0.96, 95% CI 0.70–1.30) after matching. Conclusion In patients requiring actual PVR, NAC successfully modifies the tumor–vessel interface, reducing intimal invasion and improving margin clearance while lowering blood loss, but does not translate into an independent survival benefit. This suggests that the absolute requirement for venous resection marks an aggressive phenotype where outcomes are primarily dictated by disease biology.