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Background: The aim of this study was to evaluate risk factors associated with difficult heparin reversal by protamine after cardiopulmonary bypass.Methods: Data from 120 consecutive patients who underwent open heart surgery from 2009 to 2017 were retrospectively reviewed. Patients were divided into 2 groups: (1) those in whom complete heparin reversal was achieved after a single infusion of protamine (group A, n=89); and (2) those who required more protamine for heparin reversal (group B, n=31).Results: Female sex, prolonged bypass time (>200 min), long aortic cross-clamping time (>120 min), and a lowest rectal temperature <26°C were significant predictors of difficult heparin reversal. Larger amounts of fresh frozen plasma and platelet concentrate were transfused in group B than in group A.Conclusion: Surgeons’ efforts to reduce operative time and avoid deep hypothermia may be helpful for increasing the likelihood of easy heparin reversal, especially in female patients.