Background: Immunotherapy for cedar pollinosis makes use of multiple injections of allergens, but its effectiveness remains controversial. Recent studies indicate that immunization with certain protein antigens and immunostimulatory DNA sequence (ISS) oligodeoxynucleotides (ODNs) represent a potential approach to allergen-specific immunotherapy. Objective: We determined whether the coadministration of 2 major protein allergens, Cry j 1 and Cry j 2, of Japanese cedar pollen and ISS-ODN (5′-TGACTCTGAACGTTCGAGATGA-3′) improves the immune responses induced by protein allergens in BALB/c mice. Methods: Mice were primed intradermally with allergens or ISS-ODN in saline solution and boosted with allergens in alum, and other mice were primed with allergens in alum and boosted with allergens/ISS-ODN. Allergen-specific IgG2a and IgG1 antibody responses were measured by means of ELISA in sera after ODN injection, and allergen-specific IgE antibody production was measured by the passive cutaneous anaphylaxis reaction. IFN-γ and IL-4 releases were also measured by ELISA in the supernatants of allergen-stimulated spleen cells. Results: The coadministration of allergens/ISS-ODN increased IgG2a titers and IFN-γ release in both groups of mice, whereas it decreased IgG1 titers and IL-4 release in comparison with control mice injected with allergens/mutant ODN. The coadministration additionally inhibited IgE antibody production. Conclusion: The data demonstrate that the coadministration of cedar pollen allergens and ISS-ODNs before secondary T_H2 and IgE responses or during ongoing primary T_H2 and IgE responses brings about a T_H1-shifted immune response and inhibition of IgE antibody production, suggesting that this coadministration strategy may provide a novel type of immunotherapy for cedar pollinosis. (J Allergy Clin Immunol 1999;1231-8.)