Introduction Vascular resection during pancreatoduodenectomy (PD) is being performed more frequently. Our aim was to analyze the outcomes of PD with and without vascular resection in a large, multicenter cohort. Methods Patient data were gathered from 43 institutions as part of the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) Pancreatectomy Demonstration Project. Over a 14-month period, 1414 patients underwent PD without (82.2%) or with major venous (PD + V; 13.7%) or arterial (PD + A; 4.0%) vascular resection. Results Postoperative morbidity and mortality following PD + A (51.0% and 3.6%) was comparable to PD + V (46.9% and 3.6%) and PD (44.3 and 1.5%, p = 0.50 and 0.43). A propensity score matched analysis revealed that vascular resection was associated with significant increases (p ≤ 0.05) in operative time (7:37 vs 6:11), need for blood transfusion (42.2% vs 18.1%), deep venous thromboembolism (6.9% vs 0.9%), postoperative septic shock (6.9% vs 1.7%), and length of stay (12.2 vs 10 days) while overall morbidity (45.7% vs 46.6) and mortality (1.0% vs 0%) were comparable. Conclusions Compared to PD alone, PD + VR was associated with increased operative time, perioperative transfusions, deep venous thrombosis, septic shock, as well as length of stay, but overall morbidity and mortality were not increased.