Systemic heparinization is necessary before cardiopulmonary bypass (CPB) in cardiac surgery, and protamine administration to neutralize heparin for hemostasis is required at the end of CPB. Because protamine is an allogeneic protein extracted from the sperm of specific fish, serious adverse reactions can occur during clinical application, with potentially catastrophic outcomes. A male patient received aortic valve replacement with CPB. Severe allergic reactions occurred postoperatively after protamine administration for neutralization. Emergency heparinization and CPB re-establishment were conducted with no further hemostatic treatment with protamine. However, the patient suffered a massive hemorrhage and was treated symptomatically with blood transfusion and rehydration. Following two thoracotomies for hemostasis, the patient healed and was eventually discharged. Protamine is irreplaceable as the only hemostatic that neutralizes heparin for cardiac CPB at present. However, because it is an alloprotein, it can cause serious allergic reactions after entering the human body, and caution should be exercised during the process of its clinical application.