To measure health-related quality of life (HRQL), its determinants, and its association with patient and caregiver productivity among a sample of haemophilia patients with inhibitors in the United States (US). Data on demographical and clinical characteristics, treatment patterns, HRQL (SF-12v2), and productivity outcomes were reported for 53 patients. Mean SF-12v2 domain and mental (MCS) and physical (PCS) component summary scores were assessed and compared with US norms. Regression analyses explored the association of patient and treatment factors with HRQL and productivity. Patients' mean age was 20.7 years (SD = 18.8), 88.5% were type A, and 39.6% received on-demand therapy as their only mode of treatment. Mean PCS was significantly lower than the US norm (PCS, 39.9, P < 0.01) and mean MCS showed no significant difference (MCS, 49.9, P = ns). On-demand treatment (B = -0.336, P < 0.05) and number of haemorrhages (B = -0.366, P < 0.05) were negatively associated with PCS; and PCS was associated with patients' missed work or school days [incidence rate ratio (IRR) = 0.93, P < 0.001] and perceived impact on daily activities (OR = 0.72, P < 0.05). Younger age (IRR = 0.91, P < 0.01), lower PCS (IRR = 0.94, P < 0.01), more haemorrhages (IRR = 1.05, P < 0.05), and surgery (IRR = 2.74, P < 0.05) were associated with fewer patients' productive days. Physical functioning among inhibitor patients in the US is compromised and is negatively associated with their daily activities and productivity. These data suggest a positive association of prophylactic and immunotolerance therapy with HRQL, specifically physical impairment.