The calculation of the return on investment (ROI) allows the estimation of the opportunity cost of a series of interventions and can therefore help to make allocative choices. The objective of this study is to estimate the ROI of three vaccinations (HPV for adolescents, HZ for adults, and influenza for the elderly) in the Italian context, considering the impact of increasing vaccination coverage based on target objectives of the National Immunization Plan (PNPV) 2017–2019 and accounting for different eligibility criteria of each vaccination. Three separate static cohort models were constructed, including the eligible population for these vaccinations on the basis of the PNPV 2017–2019 and following this population until death (lifetime horizon) or until vaccination waning. Each model compares the level of investment at current vaccine coverage rates (current VCRs scenario) with that of optimal NIP target VCRs with a non-vaccination scenario. The ROI for HPV vaccination was the highest among the programs compared and was always above 1 (range: 1.4–3.58), while lower values were estimated for influenza vaccination in the elderly (range 0.48–0.53) and for vaccination against HZ (range: 0.09–0.27). Our analysis showed that a significant proportion of savings generated by vaccination programs occurred outside the NHS perspective and might often not be estimated with other forms of economic evaluation.