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Objective Human papillomavirus (HPV) vaccines and DNA testing roll out in resource-constrained settings. We evaluated the natural history of HPV infections in African women to contribute to normative guidance. Methods Women aged 16 to 35 years were enrolled from 3 sites in South Africa and Kenya and followed quarterly for 18 months. A subset was recalled 5 years postenrollment, when Papanicolaou smears were conducted. Endocervical swabs were tested for 36 HPV genotypes by HPV Direct Flow. Logistic regression models identified correlations between demographic, biological, or behavioral factors and baseline high-risk HPV (HR-HPV). Results At enrollment, 158 of 311 women (median age, 23 years; IQR, 20–27) had at least 1 HR-HPV genotype. HPV-52 (13.5%), HPV-16 (9.5%), HPV-58 (9.0%), HPV-18 (8.4%), and HPV-35 (8.4%) were most common. Coinfection with low-risk HPVs (odds ratio, 2.65; 95% CI, 1.59–4.45) were associated with HR-HPV positivity, while reported condom use (odds ratio, 0.57; 95% CI,.34–.98) and older age were protective. Of women with HR-HPV at enrollment, 87.3% cleared at least 1 HR-HPV infection over 18 months and 64.6% cleared all such infections. Few (1.9%) had evidence of high-grade cervical abnormalities, among which HPV-35 was the most prevalent during the study. Conclusions The high prevalence of HR-HPV emphasizes that HPV vaccination, screening, and testing campaigns in Africa are important. Nonvaccine HPV-35 was as common as HPV-18, suggesting the need to supplement current vaccines with this genotype. HR-HPV clearance was also common, highlighting that clear messaging is needed from health care providers to patients while discussing HPV DNA testing results. [ABSTRACT FROM AUTHOR]