The study goal was to determine the technical feasibility and outcomes associated with pancreaticoduodenectomy for periampullary malignancies with near (>80%) or complete (100%) superior mesenteric venous (SMV) obstruction. A retrospective examination of 11 patients with high-grade or complete SMV obstruction who underwent pancreaticoduodenectomy at five academic medical centers is reviewed. Pancreaticoduodenectomy for locally advanced periampullary malignancies causing high-grade or complete SMV obstruction is technically feasible. Operative approaches and outcomes are presented. One 30-day death was observed. Median survival of the cohort is 18 months. Survivals exceeding 2 years post-resection have been observed. In a number of cases, significant palliation of pain and of biliary and duodenal obstruction were achieved. Based on this initial series, pancreaticoduodenectomy in the presence of near or total SMV obstruction is feasible, may result in an R0 resection, and may be beneficial in select patients with a periampullary malignancy. We suggest such an approach be considered particularly following completion of neoadjuvant therapy without systemic progression. Further studies and more long-term follow-up at high-volume centers are required, however, to better determine the indications and potential benefit of such an undertaking.