Cow's milk allergy (CMA) is one of the leading causes of food allergy in children. Understanding the mechanisms involved in the development of CMA has been hampered by the lack of suitable animal models.We sought to develop a mouse model of IgE-mediated cow's milk hypersensitivity (CMH) that mimics the clinical features of immediate CMA in humans.Three-week-old C3H/HeJ mice were sensitized by intragastric administration of cow's milk (CM) plus cholera toxin and boosted 5 times at weekly intervals.CM-specific IgE antibody levels were significantly increased at 3 weeks and peaked at 6 weeks after the initial feeding. Intragastric challenge with CM at week 6 elicited systemic anaphylaxis accompanied by vascular leakage, significantly increased plasma histamine, and increased intestinal permeability to casein. Histologic examination of intestinal tissue revealed marked vascular congestion, edema, and sloughing of enterocytes. The role of IgE in mediating CMH was confirmed by abrogation of passive cutaneous anaphylaxis reactions by heat inactivation of immune sera. Development of IgE-mediated CMH in this model is likely to be TH2 cell mediated because in vitro stimulation of spleen cells from mice allergic to CM induced significant increases in the levels of IL-4 and IL-5, but not IFN-gamma.This model should provide a useful tool for evaluating the immunopathogenic mechanisms involved in CMA and for exploring new therapeutic approaches.