Summary. An HLA‐DRA‐DRB1*0101‐restricted T‐cell epitope in the factor VIII (FVIII) C2 domain occurred in a mild haemophilia A patient with missense substitution FVIII‐A2201P. His T cells responded to synthetic peptides FVIII2186–2205 and FVIII2194–2213 (J Thromb Haemost 2007; 5: 2399). T cells from family members with genotype FVIII‐A2201P were analysed to determine if FVIII‐specific T cells occur in individuals with a haemophilic mutation but no clinically significant inhibitor response. Fluorescent MHC class II tetramers corresponding to subjects’HLA‐DRB1 types were loaded with 20‐mer peptides and utilized to label antigen‐specific CD4+ T cells. T‐cell responses to peptides spanning the FVIII‐C2 sequence were evaluated. T cells recognizing specific peptides were cloned, and antigen specificity was verified by proliferation assays. Plasma and/or purified IgG samples were tested for FVIII inhibitory activity. CD4+ T cells and T‐cell clones from two brothers who shared the DRB1*0101 allele responded to FVIII2194–2213. A haemophilic cousin’s HLA‐DRA‐DRB1*1104‐restricted response to FVIII2202–2221 was detected only when CD4+CD25+ cells were depleted. A great uncle and two obligate carriers had no detectable FVIII‐C2‐specific T cells. Concentrated IgG from the brother without a clinical inhibitor response showed a low‐titre FVIII inhibitor. FVIII‐specific T cells and inhibitory IgG were found in a previously infused, haemophilic subject who had a sub‐clinical FVIII inhibitor. CD4+CD25+ depleted T cells from a non‐infused haemophilic cousin recognized an overlapping FVIII epitope, indicating a latent HLA‐DRA‐DRB1*1104‐restricted T‐cell response to FVIII. Specific T‐cell responses to FVIII can occur without clinically significant inhibitors.