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Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome. We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing. We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59–71.30) and 4.25 times higher (95 % CI, 1.53–12.3) among carriers of F8 large deletions and small insertions and deletions, respectively. F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure. [Display omitted] • The role of F8 variants in immune tolerance induction (ITI) outcome has not been fully explored. • We assessed the F8 genotype in 168 people with severe hemophilia A and high-responding inhibitors. • Compared to Int22inv, ITI failure was ~15 times higher among carriers of F8 large deletions. • Compared to Int22inv, ITI failure was ~4 times higher among carriers of F8 small insertions/deletions. • F8 large deletions and small insertion/deletion are predictors of ITI failure in severe hemophilia A. [ABSTRACT FROM AUTHOR]