A 23–year‐old man with sickle cell anemia and multiorgan system dysfunction was treated with plasma exchange during a sickle cell crisis. The patient failed to respond to conventional treatment including hydration, blood transfusions, broad spectrum antibiotics, supplemental oxygen, and analgesics. The clinical picture resembled thrombotic thrombo‐cytopenic purpura (TTP), and the patient responded dramatically to plasma exchange with reversal of a rapidly deteriorating clinical state. This case illustrates possible similarities in the pathophysiology of TTP and sickle cell crisis, and the value of plasma exchange in related critical disease states.