OBJECTIVES: To compare the cost of treatment for three “on-demand” treatment regimens using recombinant activated Factor VII (rFVIIa [NovoSeven®]) and activated prothrombin-complex concentrate (APCC [FEIBA® VH]) for home treatment of minor-to-moderate bleeds in hemophilia with inhibitors. METHODS: A decision analytic model was developed from the payer's perspective to calculate the projected cost per bleeding episode and the 1-year cost of treatment for three “on-demand” treatment strategies consisting of first, second, and third-line treatments: rFVIIa/rFVIIa/rFVIIa, APCC/rFVIIa/rFVIIa, and APCC/APCC/rFVIIa. Published literature was used to define treatment algorithms, number of bleeds, dosing, costs, efficacy, and re-bleeds. Evaluable bleeds controlled with rFVIIa and APCC ranged from 88-93% and 78-81%, respectively. Number of bleeds was assumed to be 15 per year (range 10-20). Drug costs were based on 2005 U.S. average wholesale prices; other direct medical costs reflected 2005 values. Univariate and probabilistic sensitivity analyses (PSA) were conducted on key variables to ascertain model robustness. RESULTS: The cost per bleed (and 1-year cost of treatment) per patient was $28,076 ($421,137), $30,883 ($463,251), and $32,150 ($482,253) using rFVIIa/rFVIIa/rFVIIa, APCC/rFVIIa/rFVIIa, and APCC/APCC/rFVIIa, respectively. Annual cost offsets ranging from $42,115-$61,116 per patient occurred for the rFVIIa-only regimen through avoidance of second and third lines of treatment. Univariate sensitivity analyses showed consistent results with the base case. In PSA, the rFVIIa-only strategy was less expensive than either alternative in 68% of 10,000 model simulations. CONCLUSIONS: The management of minor-to-moderate bleeds extends beyond the initial line of treatment, and should include the economic impact of rebleeding over multiple lines of therapy. The annual cost of treatment for minor-to-moderate bleeds in a hemophilia patient with inhibitors is very high. When considering the impact of rebleeding over multiple lines of treatment, the rFVIIa-only regimen, versus APCC-containing strategies, may provide cost savings of up to $60,000 annually per patient.