Men who have sex with men (MSM) are at a higher risk of anal cancer caused by the human papillomavirus (HPV). Among young MSM with HIV, very little is known about the prevalence of low-grade squamous intraepithelial lesions (LSILs) and the anal cancer precursor, high-grade squamous intraepithelial lesions (HSILs) (MSMLWH). HPV vaccination is advised in this group, although its security, immunogenicity, and prevention against vaccine-type HPV infection and linked LSILs/HSILs have not been investigated. A total of 260 MSMLWH aged 18–26 years were tested for a clinical trial of the quadrivalent (HPV6,11,16,18) HPV (qHPV) vaccine at 17 US sites. Those who did not have HSILs received vaccinations at 0, 2, and 6 months. At screening/month 0 and months 7, 12, and 24, cytology, high-resolution anoscopy with biopsies of lesions, serology, and HPV testing of the mouth/penis/scrotum/anus/perianus were conducted. The most apparent cause for exclusion among the 260 MSMLWH examined was the discovery of HSILs in 88 of them (34 percent ). A total of 144 MSMLWH were involved in the study. HPV16 has been exposed to 47 percent of the participants before. There were no incident qHPV type–associated anal LSILs/HSILs among men who had never been exposed to that type, compared to 11.1, 2.2, 4.5, and 2.8 cases/100 person-years for HPV6,11,16,18–associated LSILs/HSILs among those who had been previously exposed to that type, respectively. qHPV was immunogenic and safe, with no major side effects related to the vaccine. MSMLWH was aged 18–26 who had never been exposed to qHPV vaccination types were protected from qHPV type–associated LSILs/HSILs. Given the high prevalence of HSILs, it is critical to vaccinate young MSMLWH before they are exposed to vaccine HPV types before they begin the sexual activity and undertake follow-up vaccinations.