Background: Routine human papillomavirus (HPV) immunization in Belgium is currently regionally managed, with school-aged girls receiving the 9-valent HPV (9vHPV) vaccine in Flanders and Wallonia-Brussels with a national catch-up program for females only. This study will assess whether expanding these programs to gender-neutral vaccination (GNV) with the 9vHPV vaccine is a cost-effective strategy in Belgium. Methods: A validated HPV-type transmission dynamic model estimated the potential health and economic impact of regional vaccination programs, comparing GNV versus female-only vaccination (FOV) with the 9vHPV vaccine in individuals aged 11–12 years in Flanders, GNV with the 9vHPV vaccine versus FOV with the 2-valent HPV (2vHPV) vaccine in individuals aged 12–13 years in Wallonia-Brussels, and national catch-up GNV versus FOV with the 9vHPV vaccine for those aged 12–18 years. Vaccination coverage rates of 90, 50, and 50% in both males and females were used in the base cases for the three programs, respectively, and sensitivity analyses were conducted. All costs are from the third-party payer perspective, and outcome measures were reported over a 100-year time horizon. Results: GNV with the 9vHPV vaccine was projected to decrease the cumulative incidence of HPV 6/11/16/18/31/33/45/52/58-related diseases relative to FOV in both Flanders and Wallonia-Brussels. Further reductions were also projected for catch-up GNV with the 9vHPV vaccine, including reductions of 6.8% (2,256 cases) for cervical cancer, 7.1% (386 cases) and 18.8% (2,784 cases) for head and neck cancer in females and males, respectively, and 30.3% (82,103 cases) and 44.6% (102,936 cases) for genital warts in females and males, respectively. As a result, a GNV strategy would lead to reductions in HPV-related deaths. Both regional and national catch-up GNV strategies were projected to reduce cumulative HPV-related disease costs and were estimated to be cost-effective compared with FOV with incremental cost-effectiveness ratios of €8,062, €4,179, and ...