A growing body of clinical experience supports the use of liver-directed recombinant adeno-associated virus (rAAV) as a gene therapy vector for the treatment of hemophilia B and, more recently, hemophilia A.1, 2, 3, 4, 5 Two primary obstacles have slowed AAV-fVIII vector development for hemophilia A compared to similar AAV-factor IX (fIX) vectors designed for hemophilia B. These obstacles include the limited DNA packaging capacity of the AAV for the large fVIII transgene size6, 7, 8 and the inefficient biosynthesis of human fVIII transgene products in heterologous target cells.9 This evidence concerns the gene F8 and hemophilia A.