Hemophilia A (HA) is a congenital bleeding disorder characterized by a deficiency of coagulation factor VIII (FVIII). For decades, the mainstay of hemophilia treatment has been replacement therapy with infusions of FVIII concentrates. However, when replacing the missing factor, approximately one-third of individuals with severe HA develop neutralizing antibodies (inhibitors). Previous studies have highlighted the complexity of the immune response to FVIII and suggested that multiple immune-regulatory genes may play important roles. From a clinical perspective, these inhibitors compromise the efficacy of infused factor, leading to increased bleeding tendency and morbidity. Immune tolerance induction (ITI) therapy is the key intervention aimed at eradicating inhibitors by providing repeated and sustained FVIII exposure, with or without the concomitant use of immunosuppressive agents, thereby promoting desensitization and tolerance. Various ITI protocols have been reported, with success rates ranging from 50% to 80%. Potential determinants of ITI outcome include ethnicity, the type of causative F8 variant, and peak inhibitor titer. In addition, recent data indicate that a family history of ITI response is independently associated with treatment success. However, despite improved understanding, much remains to be clarified regarding the decisive underlying genetic factors needed to predict the outcome of FVIII exposure. From a clinical perspective, ITI is costly and burdensome for patients and families. Therefore, in an era of new treatment options, including non-factor therapies and gene therapy, individualization of treatment will be of major importance. As emerging therapies reshape treatment paradigms, ITI continues to play a critical role in comprehensive hemophilia care. In the present study, we will focus on ITI outcomes and evaluate a combined cohort comprising participants with severe hemophilia A enrolled in the Hemophilia Inhibitor Genetics Study (HIGS) and patients treated at the Malmö Hemophilia Comprehensive Care Center, with the aim of identifying candidate genetic markers, beyond the F8 gene variant, of the immune response. Our goal is to facilitate a better understanding of the mechanisms and pathways involved and to improve the ability to predict individual outcomes, thereby supporting clinical decision-making.