The characteristic features of bronchial asthma, including airway eosinophilia and elevated immunoglobulin (Ig)E levels, are known to be orchestrated by T-helper (Th) 2 cells. Oligodeoxynucleotides containing CpG motifs (CpG) have recently been highlighted as an immunomodulator that biases toward a Th1-dominant phenotype. However, CpG may incur nonspecific Th1 activation and toxic effects. In this study we report a novel inhibition of Th2 cells by transmucosal inoculation of antigen and CpG. Intratracheal instillation of CpG inhibited airway eosinophilia and Th2 cytokine production in antigen-sensitized mice. The inhibition was observed when CpG was given at the same time or in advance of antigen challenge. Notably, concomitant administration of CpG and antigen (as opposed to either one alone) was essential for the inhibitory effects. The antigen dose could be minimized to avoid a harmful boost of eosinophilia. CpG had few effects on systemic anti-ovalbumin IgE responses. These results demonstrate that a synergism between transmucosally administered allergen and CpG inhibits Th2 cells in parallel with an improvement in airway eosinophilia and hyperresponsiveness without impeding systemic immune responses. Our data imply that inhalation of a minimal amount of allergen plus CpG could be a novel desensitization therapy for patients with bronchial asthma.