Protamine sulfate is a strongly cationic polypeptide that is used commonly in clinical medicine. It is administered regularly after cardiac catheterization, cardiothoracic and vascular surgical procedures, and less frequently after dialysis and leukapheresis because of its capacity to reverse the anticoagulant activity of heparin. In addition, because it delays the absorption of insulin, protamine is combined with insulin in protamine zinc insulin and neutral protamine Hagedorn insulin. Recently, there have been reports of adverse reactions to protamine (Table I). Although most of these reactions were relatively mild, three were fatal; one was clearly the result of type I anaphylaxis. Reactions occur predominantly in patients who were previously exposed to protamine through protamine-containing insulins or during heparin neutralization. Almost 50% of these patients were diabetic; most of whom received neutral protamine Hagedorn insulin, thereby enhancing their chance for presensitization. In 1983 we encountered three patients who suffered adverse reactions to protamine sulfate. Two of these patients will be presented here; the third patient, who died of IgE-mediated anaphylaxis, has already been reported and therefore is mentioned only briefly. We shall discuss adverse reactions to protamine sulfate and alternatives to the routine use of this drug.