Protamine is a strongly alkaline polypeptide with a molecular weight of about 4500. Protamine solutions contain paraben compounds as antimicrobial agents. Rapid neutralization of heparin by protamine may cause an anaphylactoid reaction characterized by a non-immunogenic histamine release and by unknown mediators mechanisms. This response is associated with systemic peripheral vasodilation resulting in slight to moderate hypotension. Weak negative inotropic effects by mechanisms different from the reduction of ionized calcium concentrations may also contribute to systemic hypotension. Apart from these mostly slight reactions, severe reactions may occur with life-threatening systemic hypotension, bronchospasm and, in rare cases, death. They are caused by anaphylactic/anaphylactoid reactions resulting in catastrophic pulmonary vasoconstriction which induces right and eventually global ventricular failure. Sensitization to protamine (anaphylactic) and anaphylactoid reactions are the underlying mechanisms. The majority of anaphylactic/anaphylactoid reactions are associated with complement activation and the release of anaphylatoxins C3a and C5a. These activate the cyclo-oxygenase pathway of the arachidonic acid metabolism in yet unidentified cells, probably within the lung. As a result, thromboxane and prostaglandins are released. Thromboxane is the pivotal mediator responsible for the pulmonary vasoconstriction and, presumably, also for the bronchospasm during protamine reactions. The pronounced activation of polymorphonuclear leukocytes and the decrease in platelet counts may reflect a mere epiphenomenon. The degree of right ventricular afterload increase at which systemic hypotension requiring immediate therapy would occur depends mainly on the contractile state of the heart. Potential risk patients for severe protamine reactions are depot insulin-dependent diabetics and patients with prior exposure to protamine.