The incidence of anal cancer is rising in the U.S. in both women and men. Anal cancer is more common in the general population in women than in men but is most common in HIV+ men who have sex with men (MSM). Recent data also show that anal cancer is more common in HIV+ women than HIV- women. Like cervical cancer, anal cancer is associated with human papillomavirus (HPV) and may be preceded by high-grade squamous intraepithelial lesions (HSIL). Little is known about anal HPV infection and HSIL in HIV+/- or high-risk HIV- women. In a pilot prospective study conducted in the Women's Interagency HIV Study (WIHS) in San Francisco among both HIV+ and HIV- women, anal HPV infection was more common than cervical infection. The 30-month incidence of anal HSIL among HIV+ women (20 percent) was similar to that observed in our earlier studies of FHV+/- MSM in San Francisco. This prospective study is designed to include the larger sample size of the entire WIHS cohort and has four specific aims: 1) to study the natural history of anal HPV infection among HIV+ and high-risk HIV- women in the highly active antiretroviral therapy (HAART) era; 2) study the development and progression of anal squamous intraepithelial lesions (ASIL) among HIV+ and high-risk HIV- women in the HAART era; 3) compare the natural history and risk factors for anal HPV infection and cytologic abnormalities to those of cervical HPV infection and cytologic abnormalities among HIV+ and high-risk HIV- women. Strain variants of HPV 16, 18 and 31 will be compared in the anus and cervix; and 4) analyze genetic changes in ASIL in women and compare these to cervical SIL in the same subjects. 1000 HIV+ and 300 high-risk HIV- women at the 6 national WIHS sites will be studied every 6 months with anal HPV testing, anal cytology, high resolution endoscopies and anal biopsy. Participants will be interviewed regarding behavioral and other risk factors for ASIL. These data will be analyzed in conjunction with the data already being collected at the routine WIHS visit, including cervical HPV testing, cervical cytology, CD4 levels and HIV viral load. Quantitative microsatellite analysis and array-based comparative genomic hybridization will be used to study genetic changes in ASIL. Screening for ASIL is projected to be cost-effective for anal cancer prevention in MSM. Therefore this study will have important public health implications if the data support implementation of screening for ASIL in HIV+ and high-risk HIV- women. Knowledge of genes involved in ASIL pathogenesis may provide new approaches to therapy of both anal and cervical HSIL as well as markers for disease progression.