Background: Oral human papillomavirus (HPV) infection and related oropharyngeal cancer are uncommon in lower-income countries, particularly compared to HPV-associated cervical cancer. However, little is known about the natural history of oral HPV in less-developed settings and how it compares to the natural history of cervical HPV. Methods: Three hundred fifty women aged 22 to 33 years from the Costa Rica Vaccine Trial provided exfoliated cells from the cervical and oral regions at 2 visits 2 years apart. Samples from both visits were tested for 25 characterized α HPV types by the SPF10 PCR-DNA enzyme immunoassay-LiPA25 version 1 system. Risk factors for oral HPV persistence were calculated utilizing generalized estimating equations with a logistic link. Results: Among the 82 women with characterized α oral HPV DNA detected at baseline, 14 persisted and were detected 2 years later (17.6%; 95% confidence interval [CI], 10.9–28.5%) and was similar to the persistence of α cervical HPV (40/223; 17.7%; 95% CI, 13.1–23.9%; P = 0.86). Acquisition of new α oral HPV type was low; incident infection (1.7%; 95% CI, 0.6–3.7%). Conclusions: Oral HPV DNA is uncommon in young women in Latin America, and often appears to clear within a few years at similar rates to cervical HPV.