Von Willebrand factor (VWF) and factor VIII (FVIII) circulate in a tight noncovalent complex. At present, the cells that contribute to the removal of FVIII and VWF are of unknown identity. Here, we analyzed spleen and liver tissue sections of VWF-deficient mice infused with recombinant VWF or recombinant FVIII. This analysis revealed that both proteins were targeted to cells of macrophage origin. When applied as a complex, both proteins were codirected to the same macrophages. Chemical inactivation of macrophages using gadolinium chloride resulted in doubling of endogenous FVIII levels in VWF-null mice, and of VWF levels in wild-type mice. Moreover, the survival of infused VWF was prolonged almost 2-fold in VWF-deficient mice after gadolinium chloride treatment. VWF and FVIII also bound to primary human macrophages in in vitro tests. In addition, radiolabeled VWF bound to human THP1 macrophages in a dose-dependent, specific, and saturable manner (half-maximal binding at 0.014 mg/mL). Binding to macrophages was followed by a rapid uptake and subsequent degradation of the internalized protein. This process was also visualized using a VWF–green fluorescent protein fusion protein. In conclusion, our data strongly indicate that macrophages play a prominent role in the clearance of the VWF/FVIII complex.