An 18-year-old African American man with SCD presented with acute pain crisis and fevers. He was treated with antibiotics and analgesics but developed worsening hypoxemia and mental status, requiring intubation. MRI brain showed diffuse restricted diffusion and FLAIR hyperintensities symmetrically involving bilateral cerebral deep white matter and splenium of the corpus callosum. MRA head was unremarkable, EEG showed no seizures, and CSF analysis was unremarkable. The patient was treated with hydroxyurea, voxelotor, exchange transfusion, and analgesics. Following extubation, the neurological exam remained poor with no verbal output, inability to follow commands, and spastic quadriparesis. The patient was eventually discharged to a rehabilitation facility. Monthly exchange transfusions were continued. Three months later, his neuro exam showed marked clinical improvement and near-complete resolution of subcortical and splenial white matter abnormalities on MRI. Six months later he was back to his neurological baseline.