A 65-year-old man with mitral regurgitation and atrial fibrillation underwent mitral valve plasty and Maze's operation. Cardiopulmonary bypass (CPB) was finished uneventfully. But after protamine administration, severe systemic hypotension occurred suddenly with electrocardiographic ST-segment elevation and wide QRS intervals. We thought that this reaction had been caused by coronary spasm and not by anaphylactic reaction because he was without typical anaphylactic manifestations such as general rash and bronchospasm. We administered epinephrine, methylprednisolone, heparin for restarting CPB, and used IABP support to assist systemic circulation. We again tried to administer protamine to neutralize the anticoagulative effect of heparin when his vital sign had recovered, but the same reaction occurred immediately with small amounts of protamine. The second CPB was necessary for some time. This case suggests that coronary artery spasm associated with anaphylactic reaction was induced by administration of protamine. It is known that intravenous protamine administration sometimes causes adverse events. As in this case, we should consider the possibility of severe coronary spasm associated with anaphylactoid reaction even if other symptoms of anaphylactic reactions such as cutaneous manifestation and bronchospasm are not present.