OBJECTIVE: Exagamglogene autotemcel (exa-cel) is a one-time nonviral gene-edited therapy approved in the United States (US) for treatment of patients aged ≥12 years with sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs). Standard of care (SOC) for SCD includes symptomatic care, hydroxyurea and/or red blood cell transfusions. This study estimated the long-term clinical outcomes and cost-effectiveness of exa-cel relative to SOC among patients with SCD with recurrent VOCs. METHODS: A Markov model was used to compare the expected lifetime costs and clinical outcomes of patients with SCD with recurrent VOCs treated with exa-cel versus SOC from the US payer and societal perspectives. The model structure is based on disease severity, characterized by VOC frequency, which impacts the risk of developing SCD-related complications and mortality. The model incorporated data from the phase 3 pivotal CLIMB SCD-121 trial alongside published literature. Model outcomes included number of VOCs and other acute complications, proportion of patients developing chronic complications, life years (LYs), quality-adjusted LYs (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). RESULTS: Over a lifetime horizon, exa-cel was projected to improve survival by 30.8 years (mean age of death, exa-cel: 74.5 vs. SOC: 43.6), reduce the number of VOC events by 77 (7 vs. 84), and reduce undiscounted disease-related costs by $3.34 M ($0.55 M vs. $3.89 M) compared to treatment with SOC. Patients treated with exa-cel also were less likely to experience acute complications or develop chronic complications compared to SOC. The ICER per discounted QALY for exa-cel versus SOC was $16,800 from the payer perspective; exa-cel was dominant (less costly, more effective than SOC) from the societal perspective. CONCLUSIONS: Compared to SOC, exa-cel was projected to considerably reduce the number of VOCs, improve survival, and reduce disease-related costs in patients with SCD. Exa-cel was projected to be a cost-effective treatment option.