Background & Objective: Etranacogene dezaparvovec (EDZ) is the first approved one-time gene therapy for hemophilia B, but its high upfront cost poses reimbursement challenges. This study systematically reviewed the economic value of EDZ compared with conventional factor IX (FIX) prophylaxis. Methods: PubMed and Embase were searched through 2025, following the CHEERS guideline. Original cost-utility analysis (CUA) or budget impact analysis (BIA) of EDZ were included as primary evidence, with real-world cost data as supplementary evidence. Findings were narratively synthesized. Results: Seven studies were included: three CUAs, two BIAs, and two supplementary studies. Despite heterogeneous model assumptions, all CUAs identified EDZ as dominant over FIX prophylaxis, driven by avoided long-term prophylaxis costs. BIAs projected higher upfront costs, with savings after 5–8 years depending on uptake assumptions. Supplementary evidence suggested a longer breakeven period, reflecting real-world uncertainty; a micro-costing study identified first-year monitoring as the largest non-drug cost. Conclusion: Current evidence suggests EDZ is likely a cost-saving or dominant strategy compared with FIX prophylaxis. However, most evaluations relied on short-term HOPE-B trial data with extrapolation, and real-world evidence indicates uncertainty in long-term durability. Further studies using mature real-world evidence are needed to inform reimbursement decisions.