Protamine is used for titration of heparin in vitro for diagnosis of hemorrhagic states and for neutralization of heparin in vivo to terminate heparinization. The protamine equivalent varies with the heparin preparation, conditions of testing and, in vivo, with the amount of heparin present in the circulation. The latter depends on time after administration and the hemodynamic and metabolic state of the patient. Protamine, when injected rapidly, will release histamine and agglutinate platelets. Bleeding (spontaneous hemorrhage) demonstrates a multiple breakdown of hemostatic mechanisms due to surgical stress, drugs, exposure of the blood to foreign surfaces, etc. Simple rules for the amount of protamine required for an individual patient based on clinical judgement will be satisfactory in most cases. When hemostasis is not achieved, it must be appreciated that heparin and protamine are only part of a complex deteriorating situation.