Background: Hemophilia-associated bleeding and resultant joint pain and mobility restrictions can predispose patients to poor health-related quality of life (HRQoL). Therefore, efficacy of a treatment needs to address more than just annualized bleed rates., Objectives: Describe the evolution of HRQoL, pain, and activity in patients with hemophilia A, treated with efmoroctocog alfa prophylaxis., Design: A post hoc analysis from Kids A-LONG (NCT01458106), A-LONG (NCT01181128), and long-term extension study ASPIRE (NCT01454739) assessed change in pain and activity-related patient-reported outcomes (PROs)., Methods: Physical health, pain, and HRQoL were assessed by PROs for a cumulative treatment duration of up to ~6 years. The primary endpoint was change from baseline in EuroQoL (EQ)-5D and Haemophilia Quality of Life Questionnaire (Haem-A-QoL)., Results: 118 adult/adolescents and 71 pediatric patients were included. The proportion of adults and adolescents reporting no problem in the EQ-5D analysis of ' pain/discomfort ' significantly increased from A-LONG baseline (35.04%; 41/117) to ASPIRE month 30 (44.68%; 21/47; p = 0.024). Mean (standard deviation) Haem-A-QoL subdomain scores for ' feeling ' and ' physical health ' at A-LONG baseline improved by -3.24 (15.13; p = 0.018) and -3.85 (23.07; p = 0.047), respectively, at study end. Proportion of pediatric patients reporting no problem on the EQ-5D analysis of ' pain/discomfort ', significantly increased from A-LONG baseline (75.0%; 42/56) to ASPIRE baseline (95.56%; 43/45; p = 0.046). Satisfaction levels for pediatric patients were high at A-LONG baseline and maintained until study end., Conclusion: Long-term efmoroctocog alfa prophylaxis reduces pain and improves HRQoL in adult and adolescent patients with hemophilia A. In pediatric patients, it reduces perceived pain and maintains satisfaction levels., Trial Registration: NCT01458106, NCT01181128, NCT01454739., Competing Interests: PR has received travel support to attend conferences from CSL Behring and Takeda; speaker and/or consultancy honoraria from Pfizer, Sobi, and Idogen. NK, LB, and DE are employees of SOBI AB. SL has received honoraria for speaking and reimbursement for attending symposia or congresses from Roche, Sobi, Novo Nordisk, CSL Behring, Takeda, and Sanofi. KA, SB, and MM have no conflicts to disclose., (© The Author(s), 2024.)