HPV genotype tropism and distribution is similar between the cervix and oral cavity. However, the epidemiology of HPV infection in healthy individuals is remarkably different by site, with at least 2-fold higher prevalence in the cervix compared with the oral cavity, even in women with high exposure at both sites (e.g., sex workers). While both oral and cervical HPV infection prevalence estimates are higher in women with HIV-associated immune suppression, the predominance of infection at the cervix relative to the oral cavity remains. HPV infection prevalence at the cervix is lower in older women, whereas oral HPV prevalence shows a bimodal peak at young and older ages. The cause of the prevalence differences in the oral cavity and cervix is not clear. Some current hypotheses to explain this difference include (1) sequence of site-specific exposures where infections occurring first in the genital tract offer protection in distal sites, (2) differences in immune responses by anatomic site, and (3) mechanical or cell-type differences in infection susceptibility in oral vs. cervical epithelium.