This retrospective multicenter study aimed to evaluate the risk of postpancreatectomy hemorrhage (PPH) in patients receiving antithrombotic agents (ATAs). PPH is the most severe complication after pancreatectomy. However, there is little known about the strength of the association between ATA use, PPH, and other clinical outcomes. Between 2007 and 2016, 1,297 patients underwent pancreatectomy at 2 surgical centers. ATA use included aspirin, clopidogrel, ticlopidine, warfarin, direct oral anticoagulants, and intravenous unfractionated heparin. The ATA group was composed of 144 patients who were taking ATAs before surgery. A total of 35 patients developed PPH. The patients in the ATA group showed higher frequency (8.3% vs 2.0%, p < 0.001) of PPH compared with the control group (n = 1,153). In multivariate analysis, ATA use was an independent adverse risk factor for PPH (odds ratio OR 3.58, 95% CI 1.29–9.91, p = 0.014). Stratification by preoperative ATA therapy revealed a significant risk of PPH Grade C in patients receiving combined AT therapy. The median onset of late hemorrhage (>24 hours post-surgery) in the ATA group was later than in the control group (17.5 vs 8.5 days, p = 0.032), and the incidence tended to be higher in patients who restarted ATAs postoperatively. History of ATA use is a significant risk factor for PPH, and postoperative resumption of ATAs appears to be associated with an increased risk of PPH. Patients receiving combined antithrombotic therapy may be at particularly high risk for PPH. Display omitted