AIM: This analysis aimed to assess the annual International Unit (IU) consumption and costs of prophylaxis therapies with extended half-life recombinant FVIII (EHL-rFVIII), targeting a traditional trough level of 1% and the higher levels of 3% and 5% recommended by recent guidelines and expert consensus, using a theoretical pharmacokinetic model. METHODS: A pharmacokinetic model was developed to calculate annual treatment IU consumption and costs of EHL-rFVIII products to sustain different trough levels (1%, 3% and 5%) in adult patients with hemophilia A in Italy. The model assumed a one-year perspective and assessed two scenarios: one with lower frequency of administration and one with higher frequency. RESULTS: The related annual treatment per-patient cost increased as the trough level increased. The per-patient annual cost was €117,811 to achieve a trough level of 1%, €351,543 to achieve a 3% trough level and €585,905 to achieve a 5% trough level. The increase in dose frequency (alternative scenario), that is the reduction of time between infusions, reduced the estimated doses to achieve the pre-defined FVIII levels. CONCLUSIONS: These results suggest the need for further discussion about the trough levels to target with the actual EHL-rFVIII and the prophylaxis dose and regimen selection for each patient, also considering all treatment options available and the economic implications.