Previous studies have demonstrated a high prevalence of anal cytologic abnormalities as well as anal human papillomavirus (HPV) infection among homosexual men with group IV HIV disease. However, the natural history of these changes in this population has not yet been studied. To this end, 37 homosexual men with group IV HIV disease attending an outpatient HIV clinic were followed at approximately 9-month intervals for an average of 17 months, using anal cytology, anoscopy, anal biopsy, and anal HPV DNA hybridization. During the study, the proportion of the 37 subjects with anal cytologic abnormalities increased from 27 to 65%. The proportion of subjects with any grade of anal intraepithelial neoplasia rose from 8 to 32%, with high-grade anal intraepithelial neoplasia increasing from 0 to 16%. The proportion of subjects with anal HPV infection increased from 60 to 89%, and infection with multiple HPV types was noted in at least 48%. We conclude that a large proportion of homosexual men with group IV HIV disease develop anal cytologic abnormalities, including anal intraepithelial neoplasia, over a short period of time. Together with a rapidly increasing incidence of anal cancer among single, never-married men in the San Francisco Bay area, these results suggest that these men may be at significant risk of development of anal cancer.