Background: The use of adequate adjuvants to modulate the allergic T_H2-type immune response is a promising concept for future immunotherapy of type I allergy. Bacterial DNA or oligodeoxynucleotides containing CpG motifs (CpG-ODNs) have been demonstrated to foster T_H1-type immune responses. Objective: We investigated the adjuvanticity of CpG-ODNs and their capability to modulate the allergic T_H2 response in a mouse model. Methods: BALB/c mice were treated with CpG-ODNs and Bet v 1, the major birch pollen allergen, in different experimental setups. Allergen-specific antibody responses, T_H cytokines, and eosinophilic infiltration of the airways were investigated. Results: Intraperitoneal administration of Bet v 1 together with aluminium hydroxide led to a typical T_H2 response. In contrast, coadminstration of CpG-ODNs with Bet v 1 in aluminium hydroxide resulted in markedly increased T_H1 activities (high IgG2a levels) and subsequently to reduced airway inflammation. The T_H1-like immune response indicated by these humoral findings was also reflected by decreased IL-5 and increased IFN-γ levels in cell cultures. CpG-ODNs as sole adjuvants with Bet v 1 did not lead to measureable Ig responses after subcutaneous or intraperitoneal immunizations; after intranasal application, 3 of 10 mice reacted. Nevertheless, a prophylactic effect was obtained with all routes tested; that is, mice treated subsequently with an established aerosol sensitization protocol displayed altered immune responses characterized by drastically elevated levels of Bet v 1–specific IgG2a, indicating a T_H1/T_H0-like immunity. Application of CpG-ODNs after aerosol sensitization also induced IgG2a. Conclusion: By inducing T_H1/T_H0-biased immune responses to allergens, the use of CpG-ODNs as adjuvants may have important impacts for new forms of specific immunotherapy in type I hypersensitivity. (J Allergy Clin Immunol 1999;1015-23.)