Background: Perioperative management of a patient with factor V Leiden has been infrequently reported with most studies focused in the orthopedic literature. Case Presentation: We report a case of a 74-year-old woman who underwent a pylorus-preserving pancreaticoduodenectomy without immediate perioperative embolic or thrombotic phenomena and her management throughout her hospital course. Conclusion: To the best of our knowledge, this is the first known report regarding factor V Leiden and surgical management of pancreatic ductal adenocarcinoma.