The IgE-triggered release of mast cell mediators in response to antigen is thought to be the primary event in immediate hypersensitivity reactions such as systemic anaphylaxis. Although mast cells and basophils can be activated in vitro by non-IgE stimuli, it is not known whether these triggers lead to physiological changes in vivo. To investigate this possibility, we generated mice with a homozygous null mutation of the C epsilon gene. Such mice make no IgE, but produce other immunoglobulin isotypes normally. We report that despite the IgE deficiency, sensitized mutant mice become anaphylactic on antigen challenge and display tachycardia and pulmonary function changes similar to those seen in wild-type animals. These responses are accompanied by vascular leak, sharply elevated plasma histamine and rapid death. IgE-independent anaphylaxis does not depend on complement activation, but, as indicated in studies using genetically immunodeficient RAG-2- and SCID mice, does require a functional immune system. Such results clearly demonstrate that non-IgE pathways for hypersensitivity reactions exist in mice.