Factor VIII (FVIII) is an important cofactor in the blood coagulation cascade and its deficiency or dysfunction causes Hemophilia A (HA), a bleeding disorder. Replacement with recombinant FVIII is limited by a short half-life and the development of inhibitory antibodies. We have developed a phosphatidylinositol (PI) containing lipid nanoparticle that, when associated with FVIII, reduces immunogenicity and prolongs circulation of the therapeutic protein in HA mice. Here, we conducted a multiple dose level pharmacokinetic (PK)study of human free FVIII and its FVIII-PI complex over a clinically relevant range of doses (20, 40, and 200 IU/kg) in HA mice to investigate linearity of the PK and to determine if reduced catabolism of FVIII following association with PI particles, previously only observed in the terminal phase following 400 IU/kg, could be extendable over a range of doses. Our findings suggest that the disposition of FVIII is best characterized by a two-compartment model with saturableMichaelis-Mentenelimination. Spontaneous complexation of FVIII with PI particles significantly increases plasma survival of the proteinat 20 and 40 IU/kg doses. Human simulations at 40 IU/kg project an increase in terminal half-life and time to reach a minimum therapeutic threshold of 0.01 IU/mL of 5.4 h and 40 h respectively compared to free FVIII. Formulation with PI containing lipid particles may represent a viable delivery strategy for improving FVIII therapy.