In this report, we investigated the adjuvant effect of CpG-ODN on the immunogenicity and protective efficacy of influenza M2e peptide vaccine. We found that the addition of CpG-ODN 1826 into aluminum-adjuvant M2e peptide vaccine increased M2e-specific Th1 immune response, indicated by higher titers of M2e-specific IgG2a and more IFN-gamma-secreting lymphocytes. However, according to the result from virus challenge, enhancement of M2e-specific Th1 immune response failed to increase the protection against influenza virus. Moreover, when challenged with high dose of influenza virus, the addition of CpG-ODN even weakened the protective activity. These results suggested that the intensity of immune responses was not simply correlated with protective activity of influenza M2e vaccine and more comprehensive criterion should be built up for the evaluation of M2e-based vaccine.