Individuals with immunosuppression caused by HIV infection or organ transplantation are at increased risk of human papillomavirus (HPV)-associated anogenital cancers compared with age-matched healthy individuals. The exact role of immunosuppression in conferring increased risk is not known. Although it is unknown which stages of progression from dysplasia to cancer are most affected by immunosuppression, current data suggest that immunosuppression is most strongly associated with the early stages of dysplasia, and that progression to cancer per se is not associated with immunosuppression. Studies to determine this relationship in detail are hampered by the paucity of precise biomarkers of cell-mediated immune response to HPV. This chapter will address these and other issues to provide a better understanding of the biology of HPV infection among immunocompromised individuals. Questions remain about the biology of HPV infection among immunocompromised HIV-negative individuals (e.g., transplant patients) compared with those who are HIV-positive; the impact of highly active antiretroviral therapy on the natural history of anogenital dysplasia and cancer among those who are HIV-positive, and whether the biology of specific HPV types is the same in HIV-positive as in HIV-negative individuals. Understanding HPV infection in those who are immunocompromised offers the potential to better understand its pathobiology in the putatively immunocompetent host.