Abstract High-risk type human papillomaviruses (HPV) are the underlying cause of >5% of all cancers including cervical and Head & Neck cancers in which virus-encoded E6/E7 oncoproteins serve as tumor-specific antigens. Despite the success of prophylactic HPV vaccine, therapeutic strategies targeting the E6/E7 have been ineffective in established HPV+ tumors due mainly to inadequate antigen-specific immunity. Therefore, enhancing the therapeutic potential HPV vaccines to achieve curative efficacy is an unmet clinical need. We present here preclinical evidence for efficient clearance of immunocompetent HPV tumors at the vaginal (TC-1) and oral (mEER) mucosal tissues by intranasal vaccine using HPV16 E6 and E7 short peptides along with the combination of clinically relevant adjuvants QS-21 and CpG-ODN. This vaccine exhibited high therapeutic efficacy with >80% mice with oral or vaginal tumors showing regression as well as significant extended survival advantage over untreated mice or mice treated with vaccine containing single adjuvants. The analysis of immune correlates by multicolor flow cytometry showed robust increases in the overall as well as antigen-specific (E7 tetramer+) cytotoxic CD8 T cells expressing Granzyme B and/or IFNg in both intra-tumoral and systemic compartments in vaccine-treated mice. Furthermore, the intranasal vaccine containing the combination of adjuvants induced significant frequencies of a unique subpopulation of NK cells expressing CD11c, granzyme B and IFNg, termed NKDC. Our results suggest that mucosal HPV E6/E7 peptide vaccine formulation containing QS-21+CpG-ODN adjuvants may provide an effective therapeutic strategy for the treatment of patients with HPV+ oropharyngeal and cervical cancers.