Synthetic CpG oligodeoxynucleotides (ODN) containing unmethylated CpG motifs induce macrophages to secrete IL-12, which in turn activates natural killer (NK) cells to produce interferon (IFN)-γ. These cytokines can induce T helper 1 (Th1) differentiation. In this study, the authors examined the effects of coadministering CpG ODN on the differentiation of Th responses to hen egg lysozyme (HEL) in both BALB/c (Th2-biased) and B10.D2 (Th1-biased) mice. Immunization with HEL in incomplete Freund's adjuvant (IFA) resulted in Th2-dominated immune responses characterized by HEL-specific secretion of IL-5 but not IFN-γ. However, coadministration of IFA-HEL plus CpG ODN switched the immune response to a Th1-dominated cytokine pattern, with high levels of HEL-specific IFN-γ secretion and decreased HEL-specific IL-5 production. Additionally, coadministration of IFA-HEL plus CpG ODN induced anti-HEL IgG2a, a Th1-associated isotype, which was not induced by IFA-HEL alone. Control non-CpG ODN did not induce IFN-γ or IgG2a, except for minor increases in B10.D2 (Th1-biased) mice. These results suggest that CpG ODN provide a signal to switch on Th1-dominated responses to coadministered antigen and are potential adjuvants for human vaccines to elicit protective Th1 immunity.Synthetic CpG oligodeoxynucleotides (ODN) containing unmethylated CpG motifs induce macrophages to secrete IL-12, which in turn activates natural killer (NK) cells to produce interferon (IFN)-γ. These cytokines can induce T helper 1 (Th1) differentiation. In this study, the authors examined the effects of coadministering CpG ODN on the differentiation of Th responses to hen egg lysozyme (HEL) in both BALB/c (Th2-biased) and B10.D2 (Th1-biased) mice. Immunization with HEL in incomplete Freund's adjuvant (IFA) resulted in Th2-dominated immune responses characterized by HEL-specific secretion of IL-5 but not IFN-γ. However, coadministration of IFA-HEL plus CpG ODN switched the immune response to a Th1-dominated cytokine pattern, with high levels of HEL-specific IFN-γ secretion and decreased HEL-specific IL-5 production. Additionally, coadministration of IFA-HEL plus CpG ODN induced anti-HEL IgG2a, a Th1-associated isotype, which was not induced by IFA-HEL alone. Control non-CpG ODN did not induce IFN-γ or IgG2a, except for minor increases in B10.D2 (Th1-biased) mice. These results suggest that CpG ODN provide a signal to switch on Th1-dominated responses to coadministered antigen and are potential adjuvants for human vaccines to elicit protective Th1 immunity.