An important goal of immunotherapy against human papillomavirus (HPV) infection and the cervical cancer is to control viral infection and the cancer cell growth. Here we investigate the utility of HPV 16 E7 along with CpG-oligodeoxynucleotide (ODN) for protection against HPV-immortalized tumor cells using an animal model. E7+ODN coinjection showed a significant suppression of tumor growth at both prophylactic and therapeutic levels. However, no such effect was observed without addition of both E7 and ODN. We additionally evaluated levels of immune responses by E7+ODN coinjection. E7+ODN resulted in E7-specific antibody (IgG1, IgG2a, IgG2b, and IgG3) and T-helper cell proliferative responses significantly higher than E7 alone. However, CTL responses were induced only by E7+ODN. Moreover, IFN-γ production was detected only in E7+ODN immunized groups in which IFN-γ releasing CD4+ (T-helper 1 type) and CD8+ T cells (CTL) were induced only by E7+ODN. Moreover, tumor protection appears to be mediated by CD4+ and in most CD8+ T cells, as determined by in vivo T-cell subset depletion. Taken together, these data suggest that E7+ODN codelivery could be an effective approach to induce E7-specific protective immune responses as a possible immunotherapeutic strategy for cervical cancer.