OBJECTIVES: Treating the approximately 100,000 patients in the United States today with sickle cell disease (SCD) can be costly. Identifying the main cost drivers of SCD is essential to developing appropriate interventions and improving patient outcomes. Real-world insights into the main cost drivers of SCD were gathered from the perspective of payers and physicians actively treating patients.  METHODS: A systematic literature review was conducted on resource use and cost drivers associated with SCD, guiding our questionnaire development. Three physicians from academic and private practice and nine payers (medical, pharmacy or case management directors of large regional or national plans with commercial, Medicaid and/or managed Medicaid patients) were interviewed about their SCD patient management, resource utilization, and cost drivers experiences. RESULTS: Evidence from the published literature suggests that a small number of patients account for the majority of resource utilization and costs. Studies assessing resource utilization by SCD patients reported that 25% of patients accounted for 75% (Medicaid) and 83% (privately insured) of costs, and nearly 80% of total inpatient days.  Physicians and payers indicated that about 10-30% of patients are responsible for the majority of costs. Payers also revealed that SCD patients can have “catastrophic” costs, and rank among the plan’s top 20 most costly patients. Payers and physicians all reported that SCD patients faced barriers to accessing primary care, leading to hospitalization and emergency department overuse. Barriers included low Medicaid reimbursement rates, lack of transportation, and low health care literacy.  CONCLUSIONS: Results from this systematic literature review and interviews with physicians and payers identify barriers in access to care as a key driver for hospitalization and emergency department overuse by SCD patients.  This suggests that effectively designed disease management programs can help patients avoid acute care utilization, delivering better patient care with lower costs.