Significant alterations in the circulatory properties of platelets have been documented during IgE-induced systemic anaphylactic shock in the rabbit. Within 30 to 60 sec after i.v. antigen challenge, platelet aggregation occurs in both the venous and arterial circulations. The platelet aggregates then sequester in small blood vessels of various organs, particularly in the lung. The organ sequestration results in the development of a profound thrombocytopenia within 3 to 5 min after antigen challenge. Fifteen min later deaggregation of platelets occurs and the platelets return to the peripheral circulation within normal, prechallenge levels by 60 min. Additional experiments demonstrated that platelet depletion before antigen challenge abrogates the lethal effects and significantly reduces the pathophysiologic manifestations of IgE-induced systemic anaphylaxis. We conclude that the IgE-induced platelet alterations, probably induced by the intravascular release of basophil and perhaps mast cell-derived platelet-activating factor (PAF), play a major role in the pathogenesis of systemic anaphylaxis in the rabbit.