The anaphylactic response to an i.v. injection of antigen into rabbits making only IgE antibody against the antigen was shown to be preceded by a disappearance of the metachromatic staining properties of the circulating basophils and was accompanied by marked but transient thrombocytopenia. The platelets which returned to the circulation 1 hr after the anaphylaxis were shown to be unresponsive to the secretion-inducing activity of basophil-derived platelet-activating factor (PAF) when compared with platelets examined before antigen challenge. By contrast, platelet responsiveness to other stimuli such as collagen, thrombin, and C3b was unchanged. The specific desensitization to PAF provides strong evidence for the action of this mediator on platelets in vivo during IgE-mediated anaphylaxis and provides a useful tool for detecting the effects of particular cell activators in inflammatory reactions.