Strokes in sickle cell anemia (SCA), particularly in children living in Africa, are associated with significant morbidity and an increased risk of premature death. In the US, primary stroke prevention in children with SCA involves screening for elevated transcranial Doppler ultrasound (TCD) velocity coupled with regular blood transfusion therapy for those with elevated velocities. However, regular blood transfusion therapy is not feasible in Africa due to inadequate supply of safe blood and the reluctance of parents to accept regular blood transfusion therapy for their children. Promising preliminary data from our feasibility trial in Kano, Nigeria (1R21NS080639-NCE, NCT01801423; October 2012 - August 2014) support the potential use of moderate dose hydroxyurea (HU) therapy of 20 mg/kg/day for primary prevention of stroke in children with SCA. In the feasibility trial, we screened 331 participants; 92% (25 of 27) of participants with elevated TCD measurements elected to enroll and receive HU therapy. About 75% (210 of 280) of the screened participants with non-elevated TCD measurements agreed to be followed for a minimum of three years to assess the background rate of morbidity and mortality. Among those on HU therapy, 80% (20 of 25) of the participants who reached their third month on HU therapy dropped their elevated TCD value to below 200 cm/sec in both middle cerebral arteries. Based on the results from the recently completed Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea trial (NCT01425307), demonstrating that children with an elevated TCD measurement can be switched to HU therapy after one year of blood transfusion, coupled with our preliminary trial results indicating a decrease in TCD velocities in 2/3rds of the participants over 3 months, we propose a three center randomized partial double-blind Phase III clinical trial (1R01NS094041-01; September 2015 - July 2020) to test the following hypothesis: There will be a 66% relative risk reduction of primary strokes in children with SCA, and elevated TCD measurements (n=220), randomly allocated to moderate dose vs. low dose HU therapy (10 vs. 20 mg/kg/day) for 3 years. The aims of the randomized partial double-blind Phase III clinical trial are to: 1) determine the efficacy of moderate vs. low dose HU therapy for primary stroke prevention; 2) determine the efficacy of moderate dose HU therapy for decreasing the incidence of all cause-hospitalization for any cause (pain, acute chest syndrome, infection, or other) when compared to low dose HU therapy; and 3) assess long-term safety of HU therapy (mean 6.5 years) in participants from the feasibility trial with an elevated TCD measurement (n=25), when compared to children with an initial normal TCD (n= 210, followed for at least 3 years). In preparation for this application, the teams from Nigeria have received 1 month of patient-oriented research training at Vanderbilt University School of Medicine. This trial will help us to determine whether moderate dose HU therapy can prevent thousands of strokes in children at high risk in Africa, while simultaneously helping build research capacity among the next cadre of physician scientists in Nigeria.