Sickle cell disease (SCD) is associated with endothelium dysfunction, but the role of the blood-brain barrier (BBB) in SCD has not been evaluated. We evaluated BBB function in pediatric SCD using a novel non-invasive method, water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI. Children with SCD showed lower water extraction compared with healthy individuals. Higher permeability-surface-area-product (PS), i.e. leaky BBB, was associated with a number of known abnormalities in SCD, including lower hematocrit, lower hemoglobin, higher HbS fraction, impaired cognition, and a higher risk for silent cerebral infarction. Collectively, these findings support a potential role for BBB dysfunction in SCD pathogenesis.