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Similar to any novel treatment strategy for hemophilia, gene therapy faces the question of the risk of formation of inhibitory antibodies to the therapeutic factor VIII or factor IX protein. Activation of CD4+ or CD8+ T cells could lead to antibody formation or cytotoxic T lymphocyte responses to transgene-expressing cells. Preclinical studies in animal models of hemophilia A and B with different mutations in the dysfunctional gene shed light on the risk for such immune responses and point toward strategies to avoid immune activation or even promote tolerance induction. The impacts of variables such as choice and design of gene transfer vector, underlying gene mutation, route of vector administration, and transient immune suppression are discussed. Maintenance of immunological hyporesponsiveness to the therapeutic gene product is critical for successful gene therapy. Recent studies provide evidence for tolerance induction to coagulation factor antigens by viral hepatic or neonatal in vivo gene transfer, by in utero gene delivery, and by oral or nasal administration of protein or peptides.