OBJECTIVES: To estimate the incremental cost-effectiveness ratio (ICER) of the pneumococcal non-typeable Haemophilus influenzaeprotein D conjugate vaccine (PHiD-CV) compared to the 13-valent pneumococcal conjugate vaccine (PCV-13) in routine infant vaccination in Portugal. METHODS: The cost-effectiveness analysis (CEA) is based on a Markov model simulating meningitis, bacteraemia, pneumonia and acute otitis media (AOM) in a Portuguese birth cohort until 10 years of age. CEA is performed from the National Health Service (NHS) perspective with 5% discounting on both costs and effects. The model has been parameterized using local serotype distribution, disease incidence and direct medical costs. Disutility weights come from international published literature and vaccine efficacy assumptions come from large randomized controlled trials. Model parameters have been validated by a panel of experts. Base case scenario assumes vaccination in a 2+1 schedule at 2, 4 and 12 months of age with 95% coverage. One-way and probabilistic sensitivity analyses were carried out to identify most influential parameters and estimate conjoint parameter uncertainty, respectively. RESULTS: Assuming both vaccines have the same price, the model predicts that PHiD-CV is the dominant intervention resulting in a health gain of 7 Quality-Adjusted Life Years (QALYs) and a saving of 332,151€ over PCV-13 (ICER = ‑45,216€/QALY). One-way sensitivity analysis shows ICER is very sensitive to vaccine efficacy, general practices visits and disutility, all related to AOM. The probabilistic sensitivity analysis confirms the robustness of our results with 93% of simulations showing that PHiD-CV ICER is below €30,000/QALY compared to PCV-13. CONCLUSIONS: Using PHiD-CV in the routine vaccination program for children in Portugal could generate more health benefits and savings for NHS, even when considering parity price versus PCV-13. These savings could then be used to implement other public health measures such as a catch-up program to reduce inequalities in older cohorts.