Inhibitor development is now the main complication of replacement therapy in haemophilia A. Given that most severely affected patients make no detectable factor VIII, it is perhaps surprising that only approximately 30% actually mount an immune response to factor VIII as a foreign antigen. Those that do mostly have major factor VIII gene lesions. The association of HLA genotype with inhibitors in patients with identical mutations is weak. Environmental factors may be more important than genetic in antibody response to factor VIII.