We report four patients who developed severe adverse reactions to protamine sulfate following cardiac surgery. Two types of reactions were seen. First, an immediate anaphylaxis which is a complement-dependent IgG antibody-mediated reaction. In the literature, 80% of patients who had similar reactions have had previous exposure to protamine. All patients adequately tested had positive skin tests and there is 6% mortality. The second reaction to protamine during cardiac surgery is characterized by delayed onset and profound vascular damage presenting as noncardiogenic pulmonary edema or total vascular collapse with prolonged hypotension and anasarca. These patients have negative skin tests and in our studies, no evidence of antibody mediated reaction, suggesting some other mechanisms may play a part. The mortality is high (30% of patients reported) and survivors have significant morbidity.