Summary. von Willebrand factor (VWF) has the capacity to form a complex with factor VIII (FVIII) which may modulate the immunogenicity of FVIII. It has been proposed that a significant fraction of recombinant FVIII (rFVIII) is unable to bind VWF. In an experimental model studied at the McMaster University in Canada, this VWF-unbound rFVIII fraction showed no coagulant function. Sulphation of FVIII tyrosine (Tyr) 1680 has been reported as essential for the interaction with VWF. In a study performed at the Grifols and CNS-CSIC in Spain, Tyr1680 sulphation was observed to be incomplete in rFVIII and complete in plasma-derived FVIII (pdFVIII). This could explain the incapability of some rFVIII molecules to bind VWF. Experience with immune tolerance induction (ITI) at the Bonn Haemophilia Centre indicates that only eradication of FVIII inhibitors allows safe haemostasis control and the option of prophylactic treatment. Various clinical trials were planned to evaluate the clinical role VWF-containing FVIII concentrates (FVIII/VWF). RES.I.ST (an acronym for REScue Immunotolerance STudy) is an international, prospective study aimed at assessing whether FVIII/VWF can induce ITI in high-risk haemophilia patients (RES.I.ST naïve) and whether patients who previously failed ITI with FVIII alone can be rescued with FVIII/VWF (RES.I.ST experienced). Enrolment started in November 2009. In the FAIReSt.Will (Fanhdi and Alphanate Italian Retrospective Study in Willebrand disease) study, 120 von Willebrand disease (VWD) patients treated with Fanhdi® or Alphanate® were retrospectively analysed. Efficacy was excellent and no side effects were reported. The ongoing PRO.Will study is a prospective, multicenter trial aimed at assessing the efficacy, safety and pharmacoeconomics of secondary long-term prophylaxis in patients with severe inherited VWD.