Since the use of heparin reversed by protamine is the gold standard for anticoagulation during cardiopulmonary bypass (CPB), a documented allergy to protamine represents a serious challenge for cardiac anaesthesiologists. We report here a bicentric case report of two patients with documented IgE-mediated protamine allergy requiring redo cardiac surgery. Given the high hemorrhagic risk, a perioperative desensitization strategy was implemented to enable the use of protamine at CPB termination. The protocol was initially tested in outpatient care and demonstrated excellent tolerance. During surgery, standard heparin anticoagulation was used, followed by intraoperative desensitization to allow full heparin reversal. Protamine was hemodynamically well tolerated in both cases, and postoperative recovery was uneventful. To the best of our knowledge, this is the first description of a perioperative strategy designed to induce protamine tolerance in IgE-mediated protamine allergy during cardiac surgery with CPB. This management strategy appears particularly promising, as it offers a strategy that effectively minimises the risk of haemorrhagic complications.