In conclusion, transient B cell depletion and even more so use of a codon-optimized FVIII sequence in hepatic gene transfer represent promising strategies to avoid inhibitor formation and promote tolerance in gene therapy for hemophilia A. Therefore, adding a different and superior method for tolerance induction such as hepatic gene transfer may improve the usefulness of rituximab for elimination of inhibitors in congenital hemophilia. This evidence concerns the gene F8 and hemophilia A.