Background: Sickle cell disease (SCD) is a rare hereditary blood disorder affecting approximately 100,000 individuals in the United States (US). SCD is associated with severe symptom burden, frequent hospitalizations, organ damage and increased risk of mortality. Vaso-occlusive crises (VOCs) are a hallmark clinical manifestation of SCD and often require emergency room visits and inpatient admissions. While there is some evidence describing the lifetime direct healthcare costs for SCD, the economic burden for patients with severe SCD, defined as experiencing recurrent VOCs, is currently unknown. Aims: To estimate the per-patient lifetime direct healthcare cost of severe SCD from a US payer perspective using an economic model developed based on published model frameworks. Methods: An individual-level simulation model was used to estimate the lifetime direct healthcare cost for patients with severe SCD in the US. The model followed patients with severe SCD, with an average of 7 VOCs per year, from birth until death. Similar to previously published economic models, mortality was estimated based on the occurrence of VOCs and other acute and chronic complications of SCD. Cost inputs were derived from published literature. Wholesale acquisition costs were utilized for all drug cost inputs. Scenario analyses were conducted to determine the impact of disease severity, defined by the number of VOCs per year, on the estimates of lifetime cost. The cost and impact of recently approved chronic, non-curative SCD therapies were not included in analyses. Results: The model followed patients with severe SCD for an average of 35 years, over which time each patient experienced an average of 246 VOCs. The total undiscounted cost of SCD over the lifetime was estimated to be $5.2 million. The majority of costs (77%, $4.0 million) were attributable to the care associated with acute complications, which includes VOCs, acute chest syndrome and stroke. The lifetime cost of chronic complications, including pulmonary hypertension, chronic kidney disease, retinopathy, and neurocognitive impairment, was estimated as $760,000. Scenario analyses demonstrated the lifetime costs of SCD are highly sensitive to the annual number of VOCs; when varying the average number of VOCs per year from 5 to 9, the lifetime costs ranged from $4.2 million to $6.2 million. Patients with SCD who have a significantly elevated number of VOCs (14 annually) were projected to have $8.6 million in lifetime direct healthcare costs. Summary/Conclusion: Model projections show significant lifetime economic burden with severe SCD in the US, with per-patient cost estimates substantially higher than those previously published for the overall SCD population. Treatments that can eliminate the occurrence of VOCs in this population would significantly lower this economic burden.