Background: Respiratory syncytial virus (RSV) infection remains one of the major reasons of re-hospitalization among children with congenital heart disease (CHD). This study estimated the cost-effectiveness of palivizumab prophylaxis versus placebo, in Spain, from the societal perspective, using a novel cost-effectiveness model reflecting evidence-based clinical pathways. Methods: A decision-analytic model, combining a decision tree structure in the first year and a Markov structure in later years, was constructed to evaluate the benefits and costs associated with palivizumab versus no prophylaxis among children with CHD. In the first year of the model, children were at risk of mild (i.e. medically attended, MA-RSV) and severe (hospitalized, RSV-H) RSV infection. The impact of delayed corrective CHD surgery due to RSV infection and the consequence of performed surgery despite severe infection were considered. In later years, patients were at risk of developing asthma and allergic sensitization as sequelae of RSV infection. Input data for the model were derived from the pivotal clinical trial and systematic literature reviews. Indirect costs included parental absence from work and nosocomial infections. In agreement with Spanish guidelines, costs and effects were discounted at 3%. Results: Over a lifetime horizon, palivizumab prophylaxis yielded 0.11 and 0.07 additional quality-adjusted life years (QALYs) and life years (LYs), respectively, at additional costs of € 1,693, resulting in an ICER of € 15,748 per QALY gained and € 24,936 per LY gained. Probabilistic sensitivity analyses demonstrated that the probability of palivizumab prophylaxis being cost-effective at a € 30,000 per QALY threshold was 92.7%. The ICER remained below this threshold for most extreme scenario analyses. Conclusions: The model demonstrated that palivizumab prophylaxis results in more QALYs than no prophylaxis in children with CHD. Palivizumab prophylaxis was shown to be a cost-effective health care intervention according to the commonly accepted standards of cost-effectiveness in Spain (ICER below the threshold of € 30,000 per QALY).