Patients with hemophilia who develop inhibitors present a particular challenge in therapeutic management. Although such patients are at high risk for severe bleeding episodes, the optimal treatment approach--prophylaxis--is ineffective unless inhibitors are eliminated. Several protocols for immune tolerance induction have been used. Success rates may vary depending both on patient variables and on factors related to the therapeutic regimen, including concentrate purity and von Willebrand factor (VWF) content. Several in vitro studies testing inhibitor plasma samples against various factor VIII (FVIII) concentrates have shown lower FVIII inhibitor titer compared with concentrates with greater VWF content. Recent in vivo observations also support the importance of VWF content, based on evidence of reduced rates of success of immune tolerance induction with use of the high-purity FVIII products that became available in the early 1990s. Current data thus support use of FVIII concentrates containing VWF in immune tolerance induction; other variables may also contribute to the relative success of this treatment. Studies are needed to delineate these variables in order to improve management of this potentially devastating complication of hemophilia treatment.