Hemophilia, an X-linked recessive bleeding disorder characterized by deficiencies in clotting factors VIII (Hemophilia A) or IX (Hemophilia B), leads to recurrent bleeding episodes and significant morbidity1. Traditional management involves regular intravenous infusions of clotting factors, imposing a substantial treatment burden, particularly on pediatric patients. Recent advancements, including gene therapy and novel factor replacement therapies, have shown promise in adults; however, their efficacy and safety in the pediatric population remain underexplored. This multicenter, randomized controlled trial evaluated the clinical outcomes of these advanced therapies in children aged 2–18 years with moderate to-severe hemophilia A or B. Participants were randomized into three groups: Group 1 received adeno-associated virus (AAV)-mediated gene therapy tailored to their specific deficiency; Group 2 received novel factor replacement therapy, including extended half-life recombinant factors or emicizumab for Hemophilia A; and the Control Group continued standard prophylactic factor replacement therapy. The primary outcomes assessed were the annualized bleeding rate (ABR) and post-intervention factor activity levels over 12 months. Secondary outcomes included safety profiles, quality of life improvements measured via the Haemo QoL questionnaire, and the necessity for breakthrough treatments. The gene therapy group demonstrated a statistically significant 75% reduction in ABR (p<0.001) and sustained endogenous factor production with median levels of 20 40%. The novel factor replacement group showed a 60% reduction in ABR (p<0.01) and required fewer infusions compared to the control group. Both intervention groups reported significant improvements in quality of life (p<0.05). Transient liver enzyme elevations occurred in 15% of the gene therapy group but resolved without intervention. These findings suggest that gene therapy and novel factor replacement therapies are effective in reducing bleeding rates and improving quality of life in pediatric hemophilia patients. Gene therapy offers a sustained response but necessitates long-term safety monitoring, while novel factor therapies provide effective alternatives with reduced treatment burdens. Future research should focus on optimizing dosing strategies and addressing immunogenicity concerns in this population.