Fat embolism syndrome (FES) is a known complication of sickle cell disease (SCD) that occurs secondary to vaso-occlusive crises, bone marrow infarction, and the subsequent release of fat globules into the venous circulation. Although neurologic involvement is common, the pathophysiology of cerebral fat emboli remains controversial. While fat microemboli can enter the arterial circulation through right-to-left shunts, the systemic release of free fatty acids may also cause indirect endothelial damage and disruption of the blood-brain-barrier. We present an unusual case of cerebral fat emboli in SCD that occurred in the absence of acute chest syndrome or right-to-left shunt, favoring a biochemical etiology. Treatment of FES includes supportive care and emergent red cell exchange transfusions. Keywords: Stroke, Fat embolism, Hemoglobin SC disease