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Background Human papillomavirus (HPV) causes anogenital warts and cancers in men and women. However, little is known about sex differences regarding the natural history of anogenital HPV infection. Methods Starting in May 2014, an observational cohort study including 2309 men and 2378 women aged 18–55 years was conducted in Liuzhou, China. Samples from anogenital sites were tested for HPV genotypes by multicolor real-time polymerase chain reaction and melting curve analysis biannually for ~1 year. Results The incidence of oncogenic HPV infection was similar in men and women (10.3 and 11.5/1000 person-months; P =.275), whereas the incidence of HPV-6/11 infection was higher in men than in women (2.0 vs 1.1; P =.018). The incidence of both oncogenic HPV and HPV-6/11 infections was significantly higher in women in the 18- to 25-year age group than in the older age groups (P =.006 and.011, respectively), whereas it did not vary by age among men (P =.552 and.425, respectively). Additionally, men were more likely than women to clear oncogenic infections (101.5 vs 58.6/1000 person-months; P <.001), but no significant difference was found in the clearance of HPV-6/11 by sex (111.7 vs 84.8; P =.266). The median time to clearance of oncogenic type and type 6/11 infections was not age dependent for either sex (all P >.05). Conclusions The natural history of oncogenic and nononcogenic HPV infection differs by sex, which implies that sex-specific vaccination strategies should be considered for oncogenic and nononcogenic HPV. Clinical Trials Registration NCT02188004. [ABSTRACT FROM AUTHOR]