The first and most extensively studied genetic factor is the causative FVIII gene (F8) mutation. A series of studies showed that the development of inhibitors correlates with the type and location of F8 mutations [9,12–16]. There is general agreement that patients carrying mutations, which cause severe rearrangements of F8 and preclude the synthesis of the gene product, defined as null mutations (large deletions, inversions and nonsense mutations) are more susceptible to developing inhibitors to FVIII. On the other hand, missense mutations, associated with the synthesis of an endogenous but functionally abnormal protein, usually confer a low risk of inhibitor development. Small insertions/deletions and splice site mutations are also considered lower risk genotypes, but this risk is reported more variable with respect to the location of the gene defect and its effects on the gene product. In patients with small deletions/insertions, the risk of inhibitor development is lower for mutations that occur within the A-runs compared with non-A-run abnormalities [13,15]; inhibitors were found from 17% to 44% of patients carrying splice site mutations [13–16]. Therefore, a more detailed stratification of mutation subclasses according to inhibitor risk has recently been proposed , but globally most patients carry mutations with a similar risk profile [9,13]. The Malmö International Brother Study (MIBS) clearly showed that for siblings, a family history of inhibitor development is associated with an approximately threefold higher risk to develop an inhibitor . However, this genetic susceptibility could not be predicted by the F8 mutation itself, as the overall concordance between siblings (all or none with a history of inhibitors) was 70% and 63% in all families studied and in those with the intron 22 inversion respectively [17,18]. For the latter, only 38% of all siblings had inhibitors . On the other hand, concordance in families with inhibitors was 42%, and 72% of these inhibitors had the same anamnestic (high-responding) features . Interestingly, concordance was not absolute even in monozygotic twins. The role of genetic determinants other than F8 mutations is also supported by the twofold increase in the risk of inhibitor development in non-caucasian patients , whose mutation spectrum is similar to that of causasians. In this respect, the exclusive presence of H3 or H4 FVIII haplotypes in black haemophiliacs, distinct from the H1 and H2 found in all racial groups that match the replacement FVIII products therapeutically used, have been recently proposed as a risk factor for this ethnic group . The search for other determinants of genetic susceptibility to inhibitor formation has been obviously extended to genes involved in the immune response. In spite of a key role in the recognition and presentation of FVIII for initiating the cellular response that results in inhibitor generation , conflicting results have been reported regarding a predisposition or a protective role of a variety of leukocyte antigen (HLA) alleles in this setting . Interesting data in the MIBS have been obtained by evaluating polymorphisms of genes encoding immune-regulatory cytokines. An increased inhibitor risk has been shown in patients with a microsatellite polymorphism in the promoter of the interleukin-10 (IL-10) gene compared with non-carriers , as well in patients with the homozygous −308A allele of tumour necrosis factor-α (TNF-α) gene compared with those bearing a G allele . On the other hand, a protective effect has been detected in patients with the −318C>T polymorphism of the cytotoxic T-lymphocyte associated protein-4 (CTLA-4) gene . These polymorphisms putatively modulate the cytokine synthesis/release upon antigenic stimuli, thus promoting or inhibiting the expansion of possible inhibitor-producing B-cell clones. The potential role of these polymorphic markers is further supported by their distinct ethnic distribution . On the whole, these and possibly other currently unrecognized immune-regulatory polymorphic markers may contribute to the genetic susceptibility to inhibitor development. From a clinical point of view, the stratification of genetic risk in newly diagnosed patients starting replacement treatment has been collectively referred to F8 mutation type, although the classification into high-risk and low-risk mutations is likely an oversimplification, and to the inhibitor family history, which may include other candidate or hypothesized genetic determinants .