Background When bound to mast cell FcεRI, IgE serves as antigen receptor for allergic reactions, permitting specific identification of the allergen. Although the core of the classic antigen-binding site is heavy chain complementarity determining region 3 (CDR-H3), recent studies suggest that allergens might also bind IgE in a superantigen-like fashion outside the classic antigen-binding site. Objective We sought to evaluate the contribution of the classic CDR-H3-centric antigen-binding site to the development of an allergic phenotype. Methods Using a murine model of experimental asthma, we characterized a gene-targeted mouse strain expressing an altered range of CDR-H3s (ΔD-iD mice) in response to the hydrophobic allergen ovalbumin (OVA). Mutant and wild-type (wt) mice were sensitized intraperitoneally with OVA; non-sensitized mice served as controls. Results We found the composition of the classic CDR-H3-centric antigen-binding site to be critical for the development of characteristic aspects of allergic asthma. (i) Compared with wt animals, ΔD-iD mice showed a significantly less pronounced OVA -induced rise in allergen-specific IgE levels and hence in total serum IgE levels. (ii) In addition, ΔD-iD mice demonstrated a significant reduction in eosinophilic airway inflammation, as well as in interleukin-4 (IL-4), IL-5 and IL-13 levels in BAL fluids. Conclusion Allergic sensitization and airway inflammation depend on the composition of the predominant CDR-H3 repertoire, suggesting that the classic CDR-H3-centric antigen-binding site plays a crucial role in creating the immunological interface between allergen and IgE. Our results further emphasize a central role of IgE, not only in mediating but also in regulating the allergic immune response. © 2009 Blackwell Publishing Ltd.