BACKGROUND: Cervical cancer is responsible for around one-quarter of all cancer deaths among Ghanaian women. Between 2013 and 2015, Ghana conducted a pilot of HPV vaccination among 10-14-year-old girls in four regions; however, the country has yet to introduce the vaccine nationally. This study projected the cost-effectiveness and budget impact of adding HPV vaccination into Ghana's national immunization program. METHODS: We used a proportional outcomes model (UNIVAC, version 1.4) to evaluate the cost-effectiveness of introduction with bivalent (Cervarix™) and quadrivalent (Gardasil®) vaccines from government and societal perspectives. Vaccine introduction was modeled to start in 2022 and continue over ten birth cohorts using a combined delivery strategy of school (80%) and community outreach (20%). We modeled vaccination in a single age cohort of 9-year-old girls vs. a multi-age cohort of 9-year-old girls (routine) and 10-14-year-old girls (one-time campaign) compared to no vaccination. Health outcomes included cervical cancer cases, hospitalizations, deaths, and disability-adjusted life years (DALYs). We applied a discount rate of 3% to costs and outcomes. All monetary units are reported in USD 2018. RESULTS: National HPV vaccination in Ghana was projected to be cost-effective compared to no vaccination in all scenarios evaluated. The most cost-effective and dominant strategy was vaccination among 9-year-old girls, plus a one-time campaign among 10-14-year-old with the bivalent vaccine ($158/DALY averted from the government perspective; 95% credible range: $19-$280/DALY averted). Projected average annual costs of the vaccine program ranged from $11.2 to $15.4 M, depending on strategy. This represents 11-15% of the estimated total immunization costs for 2022 ($100,857,875 based on Ghana's comprehensive Multi-Year Plan for Immunization, 2020-2024). DISCUSSION: Our model suggests that introducing HPV vaccination would be cost-effective in Ghana under any strategy when willingness-to-pay is at least 40% GDP per capita ($881). Inclusion of a one-time catch-up campaign is shown to create greater value for money than routine immunization alone but would incur greater program costs.