Hydroxyurea is increasingly used in patients with sickle cell disease and acts by several underlying mechanisms. Its usage has been reported to eliminate transfusion needs in children with beta-thalassemia major. It has also been used in sickle cell disease patients on stroke prophylaxis with exchange transfusions who develop transfusional iron overload and is now being considered as a possible alternative to chronic transfusions for secondary stroke prophylaxis. Our case demonstrates a pitfall when using hydroxyurea without monitoring intracranial cerebral vessels for vasculopathic changes; presence of which can predict stroke risk and alert the need for chronic blood transfusions as primary stroke prophylaxis. Transcranial Doppler is a crucial investigation that can reveal elevated cerebral arterial flow velocities.