Persistent infection with high-risk human papillomavirus (HPV) is a major risk factor for cervical cancer, and HPV clearance seems to be under host genetic influence. This study evaluated associations between three single nucleotide polymorphisms in the IL10 promoter and clearance of low- or high-risk HPV infection in a cohort of 226 largely HIV-1- infected African-American adolescent females. Among immunosuppressed individuals (HIV-1 seropositive and CD4+ ≤ 500), the GCC haplotype in the IL10 promoter was associated with reduced clearance of high-risk HPV16-like [relative hazard (RH), 0.46; 95% confidence interval (95% CI), 0.25-0.85; P = 0.01], HPV18-like (RH, 0.33; 95% CI, 0.16-0.67; P = 0.002), and any high-risk type (RH, 0.37; 95% CI, 0.20-0.68; P = 0.002) but not with low-risk HPV type (RH, 0.60; 95% CI, 0.29-1.25; P = 0.17). No associations were observed among immunocompetent individuals. The IL10 GCC haplotype has been associated with production of relatively high levels of interleukin (IL)-10, which could (a) inhibit cytokines such as IL-2, TNF-α, IL-4, IL-6, and IL-12 that are involved in the T H1-TH2 immunoregulation; (b) down-regulate expression of MHC class I and class II molecules; or (c) induce the transcription of early promoter of HPV, all potentially contributing to duration of HPV infection among immunosuppressed individuals. These results support the hypothesis that IL10 polymorphisms influence the clearance of infection with high-risk HPV types and warrant further studies of host genetic control of HPV pathogenesis and cervical cancer in the context of immunosuppression. Copyright © 2007 American Association for Cancer Research.