Primary prevention by the FDA-approved HPV vaccines (2-valent, 4v, and 9v vaccines) has the potential to reduce the incidence and mortality attributable to the HPV-positive oropharyngeal (OPC) and anogenital cancers, while the role of secondary prevention through HPV-based screening for oropharyngeal cancer has not been established. Although the real-world data about the effectiveness of HPV vaccines for the prevention of cervical cancer was recently reported in NEJM, the direct role of HPV vaccine for OPC prevention has yet to be clarified though long- term, large-scale longitudinal evidence. However, at least, the effectiveness of HPV vaccines for oral or oropharyngeal HPV infection has been determined. Several studies have identified a significant decrease in vaccine-type oral or oropharyngeal HPV infections in HPV vaccinees across different study designs and populations. Briefly, HPV vaccines prevented approximately 80% oral HPV infections in several cross-sectional studies. Furthermore, HPV-vaccine was highly immunogenic and about 95% vaccinees had HPV16-IgG in oral fluids post-vaccination. It seems logical that HPV vaccine would eventually prevent oropharyngeal cancer with life-long effect, considering its natural history, well-established in cervical cancer. In Korea, since National Immunization Program (NIP) included HPV vaccination for 12–13- year-old girls, there remain several issues, such as covering other age groups, changing into 9v vaccines, including male population (gender neutral vaccination), and cost-effectiveness in population scope. This talk will try to cover these issues.