Background: The worldwide administration of bivalent and quadrivalent HPV vaccines has resulted in cross-protection against non-vaccine HPV types. Infection with multiple HPV types may offer similar cross-protection in the natural setting. We hypothesized that infections with two or more HPV types from the same species, and independently, infections with two or more HPV types from different species, associate with protection from high-grade lesions. Findings: We recruited a cohort of 94 HIV, HPV-positive women from Botswana, with Grade 2 or higher cervical intraepithelial neoplasia. Infections with 2 or more HPV types from a single species associated with reduced lesion severity in univariate analysis (OR = 0.41, 95\% CI 0.18-0.97, p = 0.042), when adjusted for the presence of HPV 16 or 18 types (OR = 0.41, 95\% CI 0.17-1.00, p = 0.049), or all high-risk HPV type infections (OR = 0.38, 95\% CI 0.16-0.90, p = 0.028). Infections with 2 or more HPV types from different species did not associate (OR = 0.68, 95\% CI 0.25-1.81, p = 0.435). Conclusions: Our findings show that co-infections with genetically similar HPV types reduce the likelihood of progression to high-grade lesions in HIV positive women, an effect not observed in co-infections with taxonomically different HPV types. This observation is possibly caused by an immune cross-protection through a similar mechanism to that observed after HPV vaccination.

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