The development of anti-factor-VIII-antibodies represents the most serious complication of factor VIII concentrate therapy, affecting about 30% of patients with severe hemophilia A. The genetics of the patients, comprising the factor VIII gene mutation and the immune response genes (MHC), have been shown to influence the risk of inhibitor formation. Severe molecular defects within the factor VIII gene, such as intron 22 inversions, nonsense mutations and large deletions, are associated with a 7 to 10 times higher inhibitor prevalence than less severe molecular gene defects such as missense mutations. Unexpectedly, frame shift deletions within runs of adenine nucleotides showed a low inhibitor risk, although most of them result in a stop codon. The explanation of this phenomenon is the restoration of the reading frame in some factor VIII molecules by slippage errors of the polymerase enzymes. Within most mutation types subgroups with significantly different inhibitor risks can be defined, e.g. multi domain vs. single domain large deletions, yielding a total of 10 groups with different risks of inhibitor formation. Alleles of MHC class II genes showed a less impressive influence on inhibitor development. In two studies of patients with a homogenous factor VIII gene mutation, the alleles DQA0102, DQB0602 and DR15 occurred more frequently in patients with inhibitor than without inhibitor (relative risks ranging from 1.9 to 4.0) and therefore could be assigned as risk alleles. Inflammatory processes in early childhood are under discussion as being an environmental influence factor that may modify the immune response to a foreign antigen. Fixing the genetic predisposition by gene analysis will be one important tool in the future to assess further parameters that might influence inhibitor formation.