The development of anti-FVIII inhibitory antibodies is a major obstacle to treatment of hemophilia A patients. Here, we employ the immunosuppressive properties of FVIII gene modified apoptotic syngeneic fibroblasts to reduce immune response to FVIII in hemophilic mice. We generated a fibroblast cell line from the 129Sv-FVIII KO mouse that expresses both FVIII and zeocin resistance gene. A cell line expressing only the zeocin resistance gene was also generated. Both vector modified cell lines were maintained under selective pressure and induced to apoptose just prior to infusion into 129Sv-FVIII KO mice. Mice treated with 2 intravenous infusions of FVIII expressing apoptotic fibroblasts showed up to a 79.5% reduction in Bethesda titers and significantly lower T cell responses after subsequent challenge with 4 doses of rhFVIII. Moreover, hemophilic mice pre-immunized with rhFVIII showed a 65% reduction in Bethesda titers following treatment with 4 infusions of FVIII expressing apoptotic cells. To investigate the antigen specificity of the induced immunosuppression, apoptotic fibroblast treated mice were challenged with an unrelated protein OVA. The immune response to OVA was not affected by the infusion of apoptotic cells. In adoptive transfer studies, a blunted immune response to rhFVIII could be induced in naïve mice by infusion of CD4+ splenocytes from FVIII expressing apoptotic cell treated animals. Moreover, in vitro Treg suppression assays showed that CD4+CD25+ regulatory T cells from FVIII expressing apoptotic cell treated mice were capable of inhibiting the T cell response to rhFVIII, but not to OVA. These data demonstrate that the CD4+CD25+ regulatory T cells in these mice direct antigen specific immune suppression to human FVIII.