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Since the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) for paediatric use in Portugal, pneumococcal disease incidence among children has declined. With the availability of 20-valent PCV (PCV20) and 15-valent PCV (PCV15) and the Portuguese Board of Health's decision to implement PCV20 2 + 1 into the National Immunisation Programme (NIP), the cost-effectiveness of PCV20 under 2 + 1 and 3 + 1 schedules was assessed versus PCV13 2 + 1 and PCV15 2 + 1 in Portugal. Using a Portuguese National Health Service (NHS) perspective, a Markov model with annual cycles estimated health and cost impacts of PCV20 versus PCV13 and PCV15 over 10 years, with both cost and benefits discounted at 4%. Direct effects were based on PCV13 effectiveness and 7-valent PCV efficacy studies; indirect effects were sourced from PCV13 impact studies. Epidemiologic, utility, and cost inputs were from Portuguese data, where available. Sensitivity and scenario analyses tested result robustness. The base case showed that PCV20 2 + 1 was dominant versus both PCV13 and PCV15. PCV20 2 + 1 was estimated to avert 1884 invasive pneumococcal disease (IPD) cases, 54,768 hospitalised pneumonia cases, 222,497 otitis media (OM) cases, and 8737 deaths versus PCV13 2 + 1, resulting in a quality-adjusted life year (QALY) gain of 109,092 and cost-saving of €237,294,966. PCV20 2 + 1 averted 1653 IPD cases, 42,182 hospitalised pneumonia cases, 202,735 OM cases, and 6594 deaths versus PCV15 2 + 1, resulting in a QALY gain of 83,799 and cost-saving of €199,695,659. Pairwise comparisons of PCV20 3 + 1 versus PCV13 2 + 1 and PCV15 2 + 1, including sensitivity and scenario analyses, consistently showed cost-saving results, aligning with findings from PCV20 2 + 1 analysis. PCV20 (both 2 + 1 and 3 + 1) was estimated to be cost saving and more effective versus PCV13 and PCV15. Switching from PCV13 to PCV20 in the Portuguese paediatric NIP could yield considerable clinical and economic benefits from NHS perspective. • PCV13 reduced pneumococcal disease in Portugal. • Non-PCV13 serotypes are now more prevalent. • The model compared PCV20 with PCV13 and PCV15 over 10 years. • PCV20 infant vaccination (2 + 1 and 3 + 1) dominated PCV13/PCV15 (2 + 1).