OBJECTIVES The objective was to analyze the cost-effectiveness of a national immunization program with pneumococcal conjugate vaccine (PCV): 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) and 13-valent pneumococcal conjugate vaccine (PCV-13) in Romania. METHODS A published age stratified, deterministic, and static cohort model is used. This model highlights changes in cost and quality adjusted life years (QALYs) over time. Serotype specific disease incidence, age stratified disease incidence, mortality in the population, vaccine costs and resource utilization costs were obtained from a General Practitioner reports database and epidemiological sources. The model compared identical immunization programs involving PHiD-CV and PCV-13 vaccines taking the payer perspective. A cohort of 201,104 Romanian infants was followed for four years. Same net indirect protection for invasive pneumococcal disease (IPD) was assumed for both vaccines. RESULTS With 80% vaccine uptake and 2+1 vaccination schedule, PHiD-CV dominated PCV-13 assuming price parity. Vaccination with PHiD-CV versus PCV-13 resulted in an offset for the health care budget of £22,948 (the main driver of this difference is the decrease in Acute Otitis Media (AOM) related costs – with a total of 4,663 cases prevented) and a total of 23 QALYs gained. Sensitivity analyses revealed robustness of the model results, confirmed the dominance of PHiD-CV over PCV-13 and substantiated model outcome driven by incremental efficacy of PHiD-CV in conjunction with high incidence AOM. CONCLUSIONS According to the model, implementation of PHiD-CV vaccination program for infants in Romania will offer substantial benefits in terms of cost savings and improved health compared to an identical vaccination program involving PCV-13. PHiD-CV's potential to better prevent AOM translates into incremental benefits and dominance of PHiD-CV over PCV-13 given that their impact on IPD is similar.