After intravenous infusion, factor VIII (FVIII) is stabilized in plasma through noncovalent association with von Willebrand factor (VWF) protecting it from proteolysis and cellular uptake. With a hemostatic challenge, thrombin activation releases FVIII from VWF so that it can exert its procoagulant function. The majority of infused FVIII is cleared in the liver through interaction with the low-density lipoprotein receptor–related protein (LRP) family of cell-surface receptors. A PEGylated form of FVIII would have reduced cellular uptake and a resultant prolongation of plasma half-life. The elimination of PEG-FVIII that is internalized in the hepatocyte has not been fully characterized but may follow urinary and fecal excretion routes limiting intracellular accumulation.