OBJECTIVES: The decision to use a drug first-line instead of second-line (salvage therapy) could have a significant clinical outcome and economic impact especially in rare diseases with high treatment costs such as acquired haemophilia. The aim of this study is to compare the cost-effectiveness of first-line versus second-line use of recombinant activated factor VII (rFVIIa) in the management of severe bleeds in patients with acquired haemophilia. The perspective of the study is that of the United States hospital authorities. METHODS: We modelled the economic impact of different treatment strategies reported from the only existing compassionate-use database containing data from 38 patients with acquired haemophilia for whom rFVIIa was used in the management of 78 severe bleeding episodes from 1990–1995. RESULTS: In 14 bleeds, rFVIIa was used as the first-line therapy with 100% success in controlling the bleeds, while a success rate of 75% was reported for 64 bleeding episodes in which rFVIIa was used as a salvage therapy. The mean treatment cost of rFVIIa as the first-line therapy was $362,906 compared to $416,793 when rFVIIa was used as a salvage therapy. Furthermore, the cost per effectively treated bleed for the second-line strategy was $545,113 compared to $362,468 for first-line use. CONCLUSIONS: Based on these results, rFVIIa, as a first-line therapy, is the cost-effective treatment option in the management of severe bleeding episodes in acquired haemophilia patients as compared to second-line treatment strategies.