Since their discovery as the etiologic agents of cervical cancer in the mid-1970s, human papillomaviruses (HPVs) have been linked with a growing number of epithelial-derived tumors, including head and neck squamous cell carcinomas. HPV demonstrates a particular predilection for causing tumors of the oropharynx, with the majority of cases involving infection with high-oncogenic risk HPV-16. People living with HIV are at increased risk of infection with HPV- and HPV-related oral complications even with adequate control of their HIV infection with antiretroviral therapy. In this chapter, we discuss the molecular mechanisms that underlie HPV-mediated oncogenesis in the oropharynx. We also describe the progress that has been made in understanding the epidemiology of oral HPV infection and the determinants of oral HPV-related pathology. Finally, we examine what can be done to treat and prevent oral HPV infection, benign lesions, and cancer, particularly in the context of the HIV-positive patient.