OBJECTIVES:: New vaccines can be introduced in universal mass vaccination schemes using various ways (ad random, focused, or first in, first taken), but they all require a high initial investment. New optimization models combine a prioritization in vaccine selection with measuring the return on investment (ROI). We applied this approach for Colombia aiming to identify the best ROI scenario. METHODS:: An optimization model is combined with a fiscal model for evaluating 3 vaccines (pneumococcal infection, rotavirus, and varicella) to be introduced among ≤5 year-old children in Colombia. The goal is to maximize quality-adjusted life years (QALYs) accumulated over a 10-year period with a fixed budget increase per year until year 9 in which the vaccine budget is sufficient to implement all vaccines. The fiscal modelling translates the clinical benefits into fiscal effects expressed as gross tax revenue and healthcare cost offsets based on morbidity and mortality reductions. Benefits are quantified using discounted cash flow analysis. The overall benefit is compared with the investments in vaccination for estimating the net present value and the ROI. The fiscal results with an optimized QALY approach are compared with an alternative introduction of the 3 vaccines within identical budget constraints. RESULTS:: Investment cost per vaccine type ranged from $10.8 million for rotavirus, $ 11.7 million for varicella, and $31 million for pneumococcal disease. At a 10% discount rate, the optimized approach led to an overall fiscal ROI of 182%. Without optimizing for maximum QALYs accumulated over the 10 years of budget investment, the return is 30% more. CONCLUSIONS:: While optimization gives the best way to reach the short-term health goal within a fixed time frame and budget constraint, ROI indicates, from a government perspective, a different strategy that gains more revenue on a life-time perspective.