OBJECTIVES: To evaluate the results of randomised controlled trials (RCTs) regarding the efficacy of human papillomavirus (HPV) vaccination in preventing male genital-related diseases. METHODS: A systematic search of English language literature using PubMed, Scopus, and Cochrane Library was performed in April 2024 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. RESULTS: Evidence from four RCTs (including 7008 male participants) support the efficacy of the quadrivalent HPV vaccine in preventing genital warts and persistent HPV infection in HPV-naïve men. The low incidence of male genital malignancies in the control groups of the reported studies lead to underpowered evidence. However, vaccination leads to durable protection with a long-term follow-up of 10 years showing efficacy of 91.8% to prevent HPV 6-, 11-, 16-, or 18-related external genital lesions (EGLs) in HPV-naïve subjects. Additionally, the quadrivalent vaccine seems to effectively reduce the detection of DNA from all four HPV types. CONCLUSION: In summary, early quadrivalent HPV vaccination demonstrates efficacy in preventing HPV infection and EGLs in males. Well controlled prospective studies are needed to confirm the long-term efficacy, specifically in cancer prevention, in all men and specific subject subgroups, and to identify the targeted population who is most likely to benefit from early vaccination.