Before the introduction of highly active antiretroviral therapy (HAART), several studies demonstrated a high prevalence of human papillomavirus (HPV) infection and associated anal intraepithelial neoplasia (AIN) in men who have sex with men, particularly in human immunodeficiency virus (HIV)-infected men with low CD4+ cell counts. Similarly high levels of anal HPV infection and AIN have been found in HIV-positive women. HIV-positive men and women are at an increased risk of developing anal cancer compared with the general population. Data suggest that there has been no reduction in the incidence of AIN after the introduction of HAART. Screening efforts have the potential to decrease the incidence of invasive anal cancer, and cost-effectiveness analyses have demonstrated the utility of anal cancer screening in select populations. Treatment for AIN remains challenging, but AIN is easier to treat when the lesions are small, and it is likely that a screening program would identify affected individuals at an earlier stage of disease.