Prevention and blocking of adverse immune reactions to FVIII in hemophilia A patients. Elimination of FVIII inhibitors in hemophilia A patients who have developed an alloimmunization to FVIII may be achieved by FVIII-specific targeting of immune effectors, for instance upon manipulation of the idiotypic network. Alternatively, immune reactions to therapeutic FVIII may be avoided in previously untreated patients by using structurally modified FVIII, of which the dominant T- and B-cell epitopes and/or structures of FVIII that mediate its internalization by APCs have been altered. Simultaneously, assessment of the inflammatory state of the patient may help clinicians to reduce risks of alloimmunization.