OBJECTIVES: Risk and consequences of inhibitor (antibodies) development in patients with hemophilia are the main safety issue in patients treated with recombinant drugs, due to its impact on health and quality of patient’s life. The objective of this study is to quantify the economical impact of treating A-hemophiliac patients developing inhibitors against factor VIII (FVIII) for the National Health System (NHS) in Spain. METHODS: An economical model was built as a decision tree allowing assigning the resource use to handle inhibitor development and its associated cost in different patient groups according to its age, treatment pattern and response profile. Data was obtained from a literature review and validated by an experts’ panel. A one-way sensitivity analysis was performed to check for results robustness.    RESULTS: The mean annual cost per patient suffering from severe hemophilia A developing inhibitors against FVIII in Spain was €567,518  (EUR 2009), 99% due to pharmacological costs. Results show an important variability, from €166,845 to €2,408,486 depending on the type of patient: its age related to its weight and adequate treatment dosage, its inhibitors’ titer (low or high-titer) and its treatment (on demand or to eradicate inhibitors). The number of bleeding episodes was the variable with the greatest impact on results. According to population data and illness incidence, a 5% increase on the risk of inhibitor development implies a new case per year in Spanish population and, therefore, an expenditure of more than half a million Euro for the NHS.  CONCLUSIONS: This study analyzes for the first time the cost of inhibitors’ development among patients with severe hemophilia A treated with recombinant FVIII from the perspective of the Spanish NHS. Results show that treatments to overcome this safety issue represent an important economical burden, so that strategies preventing from inhibitor development should be implemented in this population.