Factor VIII is tightly noncovalently linked to von Willebrand factor (vWF) in plasma with a stoichiometry of 1:50, and vWF deficiency results in secondary factor VIII deficiency, with accelerated clearance of factor VIII from the circulation. We used a murine model of severe von Willebrand disease (vWF knockout mice) to study the effect of a recombinant vWF/pro-vWF preparation (rpvWF) on factor VIII survival and to investigate whether low-density lipoprotein receptor-related protein (LRP) might be involved in the in vivo clearance of factor VIII in the absence of vWF. vWF-deficient mice received 70 U/kg rpvWF in the first series of experiments, and in a second series, 80 mg/kg receptor-associated protein (RAP) as a recombinant fusion protein to block the action of LRP. Factor VIII levels were measured at time 0, or 1 or 3 hours after administration of rpvWF or RAP. RAP induced a sustained rise in factor VIII levels comparable to that induced by rpvWF. In a third series, the preadministration of RAP resulted in a slower disappearance of factor VIII antigen (measured by an enzyme-linked immunosorbent assay specific for human factor VIII) after infusion of recombinant factor VIII. These findings suggest that the accelerated clearance of factor VIII seen in the absence of vWF may be a result of the involvement of LRP in factor VIII metabolism. (Blood. 2000;95:1703-1708)