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Although most human papillomavirus (HPV) infections resolve without sequelae, some cause cervical, vulvar, vaginal, and anal cancers as well as precancerous lesions and genital warts. These lesions appear to be preventable by prophylactically administering a quadrivalent HPV-6/-11/-16/-18 vaccine to young women. This study estimated the clinical effects of vaccination in 5996 North American (US, Canada, Puerto Rico) women, most of whom were 16 to 25 years of age. Participants were culled from 5 clinical trials of nearly 22,000 women who received either quadrivalent HPV vaccine or its HPV-16 vaccine prototype. The influence of vaccination on the risk of anogenital HPV lesions was estimated in an intention-to-treat population.Women enrolled in the study had a median age of 20 years. A Papanicolaou test abnormality was present in 13% of participants. Approximately 3 of 4 women (76%) had negative test results for all 4 vaccine HPV types. After about 3 years of follow-up in the intention-to-treat population, regardless of HPV status at enrollment, vaccination lowered the rate of HPV-16- and HPV-18-related precancers by 66.4% (95% confidence interval [CI], 42.7–81.1%), and that of HPV-6/-11/-16/-18—related genital lesions by 57.7% (95% CI, 27.3%–76.3%). In general, the clinical benefit of vaccination was similar across the age range and across patterns of sexual behavior. Vaccination had a lesser effect in women who had a Papanicolaou test abnormality when vaccination began, many of whom already had HPV disease.The investigators believe that a catch-up vaccination program using the quadrivalent HPV vaccine is appropriate for North American women aged 16 to 25 years.