BACKGROUND: Two pneumococcal conjugate vaccines, covering 15 and 20 OBJECTIVE: To assess the cost-effectiveness of Pneu-C-15 and Pneu-C-20 in unvaccinated infants initiating routine pneumococcal vaccination, compared to the currently used 13-valent conjugate vaccine (Pneu-C-13). METHODS: A static cohort model was used to estimate sequential incremental cost-effectiveness ratios (ICERs in 2022 Canadian dollars per quality-adjusted life year [QALY]) of Pneu-C-13, Pneu-C-15 and Pneu-C-20 in the paediatric population starting their primary series. Costs and outcomes were calculated over a 10-year time horizon at the program level and a lifetime time horizon at the individual level and discounted at a rate of 1.5% per year. We explored the impact of uncertainties in model parameters and assumptions in scenario and sensitivity analyses. RESULTS: Routine use of Pneu-C-20 and, to a lesser extent, Pneu-C-15 is projected to reduce pneumococcal disease burden, compared to Pneu-C-13. Based on product cost assumptions, sequential ICERs for Pneu-C-15 and Pneu-C-20 were 8,800 and 35,200 per QALY gained from the health system perspective and 8,272 and 3,416 per QALY gained from the societal perspective, excluding indirect effects. A reduction in serotype-attributable disease due to indirect vaccine effects of 5% or greater resulted in ICERs below 0,000 per QALY gained for Pneu-C-15 and Pneu-C-20, with the optimal strategy determined by the magnitude and time to reach a reduction in pneumococcal disease. CONCLUSION: Both Pneu-C-15 and Pneu-C-20 are expected to increase QALYs in Canadian children compared to Pneu-C-13 and may be cost-effective interventions.