Background: To assess the role of atrial fibrillation on perioperative outcomes in patients with pancreatic cancer undergoing open pancreaticoduodenectomy (OPD). Methods: We investigated patients with pancreatic cancer undergoing OPD during 2012-2014 within National Inpatient Sample database. The study population was divided into two groups based on the presence of atrial fibrillation. In-hospital mortality, length of stay, cost of hospitalization, and in-hospital complications were compared between the two groups. Logistic regression models and linear regression were used to adjust for potential confounders. Propensity score matching was also utilized. Results: Of the 12,785 patients aged >= 18 years undergoing OPD during years 2012-2014, 11,469 (90%) had no atrial fibrillation and 1,316 (10%) had atrial fibrillation. Patients with atrial fibrillation were found to have significantly higher cost, but similar mortality and LOS compared to those without atrial fibrillation. The risk of gastrointestinal anastomotic leakage, cardiac complications, respiratory complications, pulmonary embolism, and perioperative shock were found to be significantly higher in atrial fibrillation group than non-atrial fibrillation group in both multivariate regression model and propensity score matching model. In older patients (>65 years), atrial fibrillation was found to be associated with a significantly higher cost, longer hospital stays, higher incidence of cardiac complications, respiratory complications, and postoperative shock, yet similar mortality. Conclusions: Atrial fibrillation was found to be associated with higher cost in pancreatic cancer patients undergoing OPD, as well as increased occurrence of cardiac complications, respiratory complications, pulmonary embolism, and perioperative shock. Surgeons should pay special attention to patients with atrial fibrillation, and consider working together with cardiologists and anesthesiologists to jointly develop a management plan.