To determine risk factors for squamous intraepithelial lesions (SIL) on Pap smear, 253 women at risk for human immunodeficiency virus (HIV) infection had Pap smear, HIV antibody testing, CD4+ cell measurements, and human papillomavirus (HPV) genome detection by Southern blot hybridization. Associated with SIL (P < .05) on univariate analysis were genital HPV (SIL prevalence in HPV-positive subjects, 36.3%; odds ratio [OR], 9.3; 95% confidence interval [CI], 4.2-20.3) and HIV infection (SIL prevalence in seropositive subjects, 21.9%; OR, 2.5; 95% CI, 1.2-5.1). No demographic or behavioral variables were associated with risk for SIL. Multivariate analyses identified genital HPV infection (OR, 6.78; 95% CI, 2.9-15.7), detection of known high-risk HPV types (OR, 11.8; 95% CI, 4.1-34.1), strong HPV Southern blot signal strength (OR, 10.8; 95% CI, 3.5-33.7), and severe HIV-related immunosuppression (OR, 3.1; 95% CI, 1.04-9.5) as independent risk factors associated with SIL. Thus, severe immunosuppression due to HIV infection increases the risk for SIL mediated by HPV infection.