Data from the first five years of the study show a high baseline prevalence of anal disease among HIV-positive men and a very high incidence of anal squamous intra-epithelial lesions (ASIL), including high-grade squamous intra-epithelial lesions (HSIL). With the recent advent of "highly active and retroviral therapy" (HAART), which includes protease inhibitors, possibly HIV-positive individuals will live longer, and may show a shift in the HIV epidemic from morbidity and mortality from opportunistic infections to those of more chronic diseases with a slow natural history, such as cancer. Because anal HSIL likely represents the precursor lesion to invasive anal cancer, and progression to cancer may take a number of years, the increased longevity of HIV-positive individuals due to HAART may, therefore, increase their risk of anal cancer. This is especially of concern given the preliminary data which suggest that the improved immune function associated with HAART does not lead to anal disease regression among men with ASIL before they began HAART. Thus, with the use of HAART a substantial number of HIV-positive men may be at risk of invasive anal cancer. In this renewal, the Investigator has three specific aims: (1) to study the natural history of ASIL and anal human papilloma virus (HPV) infection among patients on HAART; (2) to compare the natural history of ASIL and anal HPV infection to those not on HAART; and (3) to continue follow-up of the HIV- patients to define more fully the natural history of ASIL and anal HPV infection in these men. To reconstitute their cohort, this research group will recruit 350 new HIV-positive patients without HSIL and will continue to follow their existing HIV-positive and HIV-negative patients. The researchers will examine the men at 6-month intervals with an interview, an anal examination including cytology, HPV testing, and anoscopy with biopsy of visible disease. Blood will be obtained from HIV-positive patients for CD4/CD8 counts and HIV viral load at each visit. In all patients, additional anal examinations will be performed at 3-month intervals if anal disease is detected on cytology or histology. All patients diagnosed with HSIL will be referred for therapy. Similar to cervical cancer but unlike other malignancies related to HIV, invasive anal cancer is most likely a preventable disease. Because a large proportion of HIV-positive individuals will soon be on HAART, an understanding of the effect of these drugs on the natural history of anal disease and anal HPV infection will be essential in order to design a screening program for high risk individuals as well as better treatment and prevention efforts.