Allergic inflammation is induced by type 2 T helper cell (Th2) and Th2 cytokines such as interleukin (IL)-4, IL-5 and IL-13. These cytokines induce the production of allergen-specific immunoglobulin (Ig)E by B cells, and the ensuing degranulation of mast cells via IgE cross-linking leads to most clinical manifestations of allergic diseases. We examined the ability of immunomodulatory unmethylated CpG oligodeoxynucleotides (ODN), which are potent inducers of Th1 cytokines, to prevent allergic symptoms in mice immunized and sensitized with allergen. Coadministration of CpG ODN with ovalbumin (OVA) before OVA sensitization substantially prevented mice from allergic anaphylaxis representing enhanced circulating concentrations of OVA-specific IgE and histamine, and decreased body temperature. Although CpG ODN provokes an abundance of Th1-skewing cytokines, including IL-12, interferon (IFN)-alpha and IFN-gamma, administration of CpG ODN in IFN-gamma deficient mice inhibited IgE production and prevented from OVA-induced anaphylaxis, indicating a dispensable role of IFN-gamma in mediating these protective effects. In vitro analysis revealed that CpG ODN inhibited class switching from IgM to IgE and IgG1 in response to CD40 and IL-4 in B cells, and this effect did not correlate with up-regulation of IFN-alpha production. These results imply a B cell-intrinsic, T cell-independent mechanism by which CpG ODN directly acts on B cells and inhibits IgE and IgG1 production leading to cause prevention from allergic symptoms.