Background: The quadrivalent human papillomavirus (HPV) vaccine was shown to prevent infections and lesions related to HPV6, 11, 16, and 18 in a randomised, placebo-controlled study in men aged 16-26 years. We assessed the incidences of external genital warts related to HPV6 or 11, and external genital lesions and anal dysplasia related to HPV6, 11, 16, or 18, over 10 years of follow-up., Methods: The 3-year base study was an international, multicentre, double-blind, randomised, placebo-controlled trial done at 71 sites in 18 countries. Eligible participants were heterosexual men (aged 16-23 years) or men who have sex with men (MSM; aged 16-26 years). Men who had clinically detectable anogenital warts or genital lesions at screening that were suggestive of infection with non-HPV sexually transmitted diseases, or who had a history of such findings, were excluded. Eligible participants were randomly assigned (1:1) to receive three doses of either quadrivalent HPV vaccine or placebo on day 1, month 2, and month 6, administered as a 0·5-mL injection into the deltoid muscle. The 7-year, open-label, long-term follow-up extension study was done at 46 centres in 16 countries. Participants who received one or more doses of the quadrivalent HPV vaccine in the base study were eligible for enrolment into the long-term follow-up study (early vaccination group). Placebo recipients were offered the three-dose quadrivalent HPV vaccine at the end of the base study; those who received one or more quadrivalent HPV vaccine doses were eligible for enrolment into the long-term follow-up study (catch-up vaccination group). The primary efficacy endpoints were the incidence of external genital warts related to HPV6 or 11 and the incidence of external genital lesions related to HPV6, 11, 16, or 18 in all participants and the incidence of anal intraepithelial neoplasia (including anal warts and flat lesions) or anal cancer related to HPV6, 11, 16, or 18 in MSM only. The primary efficacy analysis was done in the per-protocol population for the early vaccination group, which included participants who received all three vaccine doses, were seronegative at day 1 and PCR-negative from day 1 through month 7 of the base study for the HPV type being analysed, had no protocol violations that could affect evaluation of vaccine efficacy, and had attended at least one visit during the long-term follow-up study. For the catch-up vaccination group, efficacy was assessed in the modified intention-to-treat population, which included participants who had received at least one vaccine dose, were seronegative and PCR-negative for HPV types analysed from day 1 of the base study to the final follow-up visit before receiving the quadrivalent HPV vaccine, and had at least one long-term follow-up visit. Safety was assessed in all randomised participants who received at least one vaccine dose. This study is registered with ClinicalTrials.gov, NCT00090285., Findings: Between Aug 10, 2010, and April 3, 2017, 1803 participants were enrolled in the long-term follow-up study, of whom 936 (827 heterosexual men and 109 MSM) were included in the early vaccination group and 867 (739 heterosexual men and 128 MSM) were included in the catch-up vaccination group. Participants in the early vaccination group were followed up for a median of 9·5 years (range 0·1-11·5) after receiving the third dose of the quadrivalent HPV vaccine, and participants in the catch-up vaccination group were followed up for a median of 4·7 years (0·0-6·6) after receiving the third dose. In early vaccine group participants during long-term follow-up compared with the placebo group in the base study, the incidence per 10 000 person-years of external genital warts related to HPV6 or 11 was 0·0 (95% CI 0·0-8·7) versus 137·3 (83·9-212·1), of external genital lesions related to HPV6, 11, 16, or 18 was 0·0 (0·0-7·7) versus 140·4 (89·0-210·7), and of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 in MSM only was 20·5 (0·5-114·4) versus 906·2 (553·5-1399·5). Compared with during the base study (ie, before quadrivalent HPV vaccine administration), during the long-term follow-up period, participants in the catch-up vaccination group had no new reported cases of external genital warts related to HPV6 or 11 (149·6 cases per 10 000 person-years [95% CI 101·6-212·3] vs 0 cases per 10 000 person-years [0·0-13·5]) or external genital lesions related to HPV6, 11, 16, or 18 (155·1 cases per 10 000 person-years [108·0-215·7] vs 0 cases per 10 000 person-years [0·0-10·2]), and a lower incidence of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 (886·0 cases per 10 000 person-years [583·9-1289·1] vs 101·3 cases per 10 000 person-years [32·9-236·3]). No vaccine-related serious adverse events were reported., Interpretation: The quadrivalent HPV vaccine provides durable protection against anogenital disease related to HPV6, 11, 16, and 18. The results support quadrivalent HPV vaccination in men, including catch-up vaccination., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests SEG reports speaker honoraria from, and being an investigator for, Merck Sharp & Dohme (MSD) Corp, a subsidiary of Merck & Co (Kenilworth, NJ, USA); being an investigator for Inovio; receiving research support from Medtronic; and being a consultant for THD America. ARG reports receiving grants from MSD paid to her institution and being a member of the scientific advisory board for MSD. JMP reports grants and travel support from MSD during the conduct of the study; grants and personal fees from, and stock options in, Vir Biotechnology; stock options in Virion Therapeutics; and personal fees from Vaccitech, outside the submitted work. MEP reports funding from MSD relating to the conduct of the vaccine trials. EDM has been an investigator for HPV vaccine studies sponsored by MSD and is a member of the scientific advisory board for MSD. EB reports clinical investigator fees for this trial. HJ reports grants and non-financial support from Klinisches Studienzentrum für Infektiologie; personal fees from Hormosan Pharma, GlaxoSmithKline, Ifi-Medizin, and CIP Clinic; grants from Sanofi-Aventis Deutschland, CROMSOURCE, Centre Hospitalier Universitaire de Nantes, and the US Military HIV Research Program (MHRP); grants, personal fees, and non-financial support from, and board membership for, Gilead Sciences; personal fees and non-financial support from, and board membership for, ViiV Healthcare and AbbVie Deutschland; and personal fees and non-financial support from MSD and Janssen-Cilag, all during the conduct of the study. HJ also reports grants, personal fees, and non-financial support from, and board membership for, Gilead Sciences; grants from CROMSOURCE, Centre Hospitalier Universitaire de Nantes, and the US MHRP; personal fees and non-financial support from, and board membership for, ViiV Healthcare and Abbvie Deutschland; and personal fees from GlaxoSmithKline, MSD, Janssen-Cilag, Ifi-Medizin, and CIP Clinic, outside the submitted work. RK reports receiving consultation fees from MSD as a member of the pathology review panel. BMR reports consulting for MSD. MHS reports personal fees from MSD, Roche, Becton Dickinson, and Inovio Pharmaceuticals as a consultant, outside of the submitted work. OB, RD, TG, AL, HJZ, and AS are employees of MSD and might own stock or stock options in Merck. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. Published by Elsevier Ltd.. All rights reserved.)