We investigated the relationship of human papillomavirus (HPV) infection of the female genital tract, cervical cytology, and human immunodeficiency virus (HIV) infection in 67 women. Forty-eight women had a history of intravenous drug use, 18 were heterosexual partners of HIV-infected intravenous drug users, and one was a transfusion recipient. Patients received a Pap smear, cervicovaginal lavage for HPV determination by Southern blot, HIV serum antibody by enzyme immunoassay with Western blot confirmation, and thorough screening for other sexually transmitted diseases. Seventeen of the 35 (49%) women seropositive for HIV had HPV infection, compared with 8 of 32 (25%) seronegative women (p less than 0.05). Fourteen of 35 (40%) HIV-positive women had squamous intraepithelial lesions (SIL) on cervical cytology, compared with three of 32 (9%) HIV-negative women (p less than 0.01). Of 22 women with symptomatic HIV infection, 11 (50%) had SIL on cytology; 10 of these 11 were HPV-positive. Among 13 asymptomatic HIV-positive women, only three (23%) had such cytological lesions. Our findings strongly suggest that HIV-induced immunosuppression exacerbates HPV-mediated cervical cytologic abnormalities.