Neonatal California White rabbits were sensitized with a glycoprotein purified from cured Virginia Bright tobacco leaves. Their serums, but not serums from normal rabbits, were demonstrated by passive cutaneous anaphylaxis technique to contain heat-labile, homocytophilic antibodies to this antigen and to similar material purified from cigarette smoke condensate. Serums containing IgE antibodies to tobacco antigen would not be demonstrated to contain hemagglutinating antibodies to this antigen. These experiments demonstrate that antigen capable of triggering specific IgE-mediated release of inflammatory mediators is present in cigarette smoke. It can be hypothesized that IgE-mediated responses to antigen in cigarette smoke are causally related to the development of vascular injury and of myocardial arrhythmia in hypersensitive smokers.