Summary. Background: Gene therapy strategies directed at expressing factor (F)VIII in megakaryocytes has potential advantages in the treatment of hemophilia A. Among these is that platelet (p) FVIII may be effective in the presence of circulating anti-FVIII inhibitors. Objective: We examined in a murine transgenic model whether pFVIII could correct the coagulation defect in FVIIInull mouse in the presence of circulating inhibitors. Methods: FVIIInull mice that were transgenic for pFVIII (pFVIII/FVIIInull) were compared with FVIIInull mice receiving infused FVIII in a FeCl3 carotid injury model in the presence of anti-FVIII inhibitors. Results: After injury, pFVIII/FVIIInull mice were significantly more resistant to circulating inhibitors than after plasma FVIII correction in both an acute and chronic models of inhibitor exposure even although in the chronic model, significant amounts of inhibitor were stored within the platelets. Furthermore, bleeding in the pFVIII mice in the presence of inhibitors was not as a result of the development of thrombocytopenia. Conclusion: In FVIIInull mice, pFVIII provides improved, but limited, protection in the presence of inhibitors of ∼6-fold greater Bethesda Units per mL relative to infused FVIII. Our findings differ from a recent report using a tail-clip exsanguination assay on the degree of efficacy of pFVIII in the presence of inhibitors. We propose that this difference in outcome is as a result of the sensitivity of the tail-vein exsanguination model to low levels of pFVIII.