Importance The disease burden of human papillomavirus (HPV)–related cancers is substantial, irrespective of sex. Establishing evidence on the effectiveness of the 9-valent HPV vaccine for males may support the implementation of sex-neutral HPV vaccination strategies. Objective To evaluate the incidence of HPV-related cancers between 9-valent HPV-vaccinated and unvaccinated males using a large-scale database. Design, Setting, and Participants This multicenter retrospective cohort study utilized a global database. Participants included males aged 9 to 26 years who were either unvaccinated or received at least one 9-valent HPV vaccine between January 2016 and December 2024 with outcomes followed-up for up to 10 years. Main Outcomes and Measures The primary composite outcomes were HPV-related cancers, including head and neck, esophageal, anal, and penile cancers. Hazard ratios (HRs) were estimated using propensity score matching. Results Before propensity score matching, 615 155 vaccinated males (mean [SD] age, 13.4 [3.5] years) and 2 290 623 unvaccinated males (mean [SD] age, 17.2 [5.5] years) were identified in the US. After propensity score matching, 510 260 participants were included in each group. Compared with those in the unvaccinated group, those in the vaccinated group had a lower risk of the primary composite outcome (HR, 0.54; 95% CI, 0.37-0.81; P = .002). Subgroup analysis demonstrated that the significantly lower incidence of the primary composite outcome in the vaccinated group was maintained among both males aged 9 to 14 years (HR, 0.58; 95% CI, 0.34-0.97; P = .04) and those aged 15 to 26 years (HR, 0.50; 95% CI, 0.27-0.93; P = .03). Conclusions and Relevance This study found a significant negative association of the 9-valent HPV vaccine with HPV-related cancers in adolescents and young adult males and contributes to the development of sex-neutral HPV vaccination.