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The objective of this study was to test whether cervical mucosal lesions and ectopy increase women's susceptibility to HIV infection.HIV-seronegative women ages 35 to 65 years (n = 5773) enrolled into a cervical cancer screening trial were followed for up to 36 months. All HIV seroconverters (n = 86) in the cohort were compared with randomly selected controls (n = 324) who did not seroconvert. Magnified photographs of the cervix taken during speculum examination at enrollment were evaluated for cervical mucosal lesions and ectopy using standard criteria.The presence of mucosal lesions (observed among 19% of controls) was associated with increased risk of HIV seroconversion (adjusted odds ratio [AOR] = 1.93; 95% confidence interval [CI] = 1.07–3.48). Ectopy extending over >20% of the cervix was also associated with HIV seroconversion (AOR = 2.18; 95% CI = 1.01–4.69).Visible lesions of cervical mucosa and cervical ectopy may be markers of increased susceptibility to HIV infection among women. Protection of the mucosa of the cervix may provide an important approach for new HIV prevention technologies.