Human papillomavirus (HPV) infection has been strongly associated with development of anogenital squamous cell cancer. Cell-mediated immunity likely plays an important role in prevention of HPV-associated disease, and HPV-associated squamous cell cancer has been shown to occur with increased frequency among iatrogenically immunosuppressed individuals. Similarly, individuals with HIV-associated immunodeficiency have been shown to have a high prevalence of anogenital HPV infection as well as a high prevalence of HPV-associated lesions that are thought to be cancer precursors. Thus, HIV-positive women have a high prevalence of cervical intraepithelial neoplasia, and HIV-positive men have a high prevalence of anal intraepithelial neoplasia. The risk of disease in these populations appears to increase as the degree of immunosuppression increases, and these individuals are likely at risk for development of invasive squamous cell cancer. Because these diseases are preventable, women should be screened on a regular basis with cervical Pap smears, followed by colposcopy if the Pap smear is abnormal. Although preliminary studies indicate that anal Pap smears may also be useful for screening, further trials need to be performed, and at this time, HIV-positive men should be assessed on a regular basis with anoscopy. Lesions that are detected should be biopsied for histopathologic assessment. Thorough assessment of the entire anogenital region should be performed because of the multicentric nature of HPV-associated diseases. Following treatment, rigorous follow-up should be maintained because of the high recurrence rate of HPV-associated disease in these populations.