OBJECTIVES: The impact of on-demand (OD) treatment for bleeding episodes is rarely quantified in Italian hemophilia patients with inhibitors. This study calculated lifetime events, hospitalizations, and quality-of-life (QoL) associated with recombinant activated Factor VIIa (rFVIIa) and plasma-derived activated prothrombin complex concentrate (pd-aPCC). This study also compared a hypothetical improved bypassing agent (BA) with faster, more sustained bleed resolution than rFVIIa against pd-aPCC. METHODS: We developed an Italian semi-Markov cohort model to reflect treatment effect on bleeds across a lifetime horizon for 2-year old hemophilia patients with high-responding inhibitors. The model tracks patients through eight health states (pre-ITI, delayed ITI, ITI low dose, ITI high dose, tolerized, partially-tolerized, non-tolerized, death) in 3-month cycles; bleeds and treatment success are simulated within states. Published international studies informed efficacy estimates, and published utility data informed QoL parameter values. RESULTS: In analysis of rFVIIa vs pd-aPCC, fewer rFVIIa patients required >1 series of home infusions per bleed (13% vs. >40% for pd-aPCC), leading to 4% fewer hospitalizations following 2+ unsuccessful home treatments. QALYs, dependent on tolerization status in the basecase, are 43.13 for rFVIIa vs. 43.06 for pd-aPCC. Exploratory comparison with improved rFVIIa bleed-resolution showed reducing the rebleed rate by 15% reduces use of >1 line of therapy by 2%, decreasing hospitalization 13% compared to basecase values. If fewer infusions of the new BA are required to control a bleed per line of therapy, patients may experience QoL benefits; utility improvement of 5%-20% raises total QALYs to 43.98-46.54 for the new BA.   CONCLUSIONS: rFVIIa may lower on-demand treatment resource use for inhibitor patients in Italy, and improving haemostasis of BAs would further improve patient care for this population; additional research around Italian treatment patterns for inhibitor patients as well as the impact of faster bleed resolution is warranted.