Chimeric human papillomavirus virus-like particles (HPV cVLP) are currently being explored as a therapeutic vaccination strategy against cervical cancer. HPV cVLP are being explored as a result of their interaction with and activation of dendritic cells, a potent antigen-presenting cell. However Langerhans cells, another type of antigen-presenting cell, can interact with HPV cVLP especially during mucosal routes of vaccine administration. Langerhans cells are not activated by HPV cVLP, utilize a different endocytosis mechanism than DC for HPV cVLP uptake, do not initiate an immune response toward HPV cVLP derived antigens, and are potentially immunosuppressive after interaction with HPV cVLP. Taken together, these findings indicate that the overall effectiveness of HPV cVLP as a therapeutic vaccine may be reduced. Bovine papillomavirus (BPV) VLP, cotton-tail rabbit papillomavirus (CRPV) VLP, and HPV VLP immune complexes (IC), which are taken up via similar endocytosis mechanisms in DC and LC, activate both cell types. DC and LC incubated with these VLP upregulate surface activation markers and increase secretion of IL-12 p70. The activated cells are then able to initiate an immune response against chimeric VLP-derived antigens. These data indicate that other therapeutic vaccination strategies based on using chimeric BPV VLP, chimeric CRPV VLP, or chimeric HPV VLP immune complexes may be more effective in generating an immune response against HPV-induced diseases such as cervical cancer.