This study examined the risk factors for genital human papillomavirus (HPV) infection, including HIV-related immunosuppression as well as demographic and behavioral factors. Subjects were 207 women with known HIV serologic status, the majority of whom were intravenous drug users recruited from a methadone treatment program in the Bronx, New York. A structured questionnaire interview, cervico-vaginal lavage, and CD4 cell measurements we're obtained. HPV genomes in the cervico-vaginal cells were detected by Southern-blot hybridization. HPV prevalence was 23% among HIV seronegatives, 45% among HIV seropositives with CD4 percent >20 and 61% among HIV seropositives with CD4 percent ≤20. Multivariate analysis identified the following independent risk factors that were significantly associated with HPV positivity: HIV-related immunosuppression, <35 years of age, and never used oral contraceptive pills. HIV-related immunosuppression was also associated with a stronger Southern-blot signal strength. HIV infection, however, did not increase the susceptibility to HPV infection with the oncogenic types (16, 18, 31, 33 and 35). Women with HIV infection or immunosuppression had a higher prevalence of HPV infection with the oncogenic types, but they also had an increased prevalence of infection with other HPV types as compared to the HIV-seronegative women. The results suggest that HIV-related immunosuppression increases the risk of genital HPV infection and has an effect on HPV replication.