Here, we utilize a spectrum of clinically relevant, epitope-mapped, FVIII-specific IgG MAbs to evaluate the role of FVIII-IC on FVIII endocytosis by BMDC and antibody responses in two murine models of hemophilia A. We demonstrate that a subset of epitope-specific FVIII-ICs alters FVIII internalization by BMDC in vitro and antibody titers in vivo through the FcγR. The gene discussed is F8; the disease is hemophilia A.