Protamine is widely used after catheter ablation to achieve hemostasis. Anaphylaxis to protamine is a rare but severe complication. A 49-year-old male patient underwent catheter ablation of symptomatic long-standing persistent atrial fibrillation. Sinus bradycardia emerged 20 minutes after the protamine infusion and was unresponsive to atropine. Subsequently, pulseless electrical activity and severe global hypokinesis developed and were refractory to pacing and repeated infusions of intravenous adrenaline. Extracorporeal membrane oxygenation and a catecholamine infusion were required for the following 2 days. An intradermal test with protamine showed positive results, and adrenaline-refractory anaphylaxis (ARA) was diagnosed. The incidence of protamine anaphylaxis is 0.14%, and ARA may occur, especially in patients receiving beta-blockers. Although there is no established approach, glucagon, methylene blue, and the rapid introduction of extracorporeal membrane oxygenation should be considered when ARA is suspected.