Cerebrovascular accident (CVA) is a major complication of sickle cell disease. The incidence and mortality of and risk factors for CVA in sickle cell disease patients in the United States have been reported only in small patient samples. The Cooperative Study of Sickle Cell Disease collected clinical data on 4,082 sickle cell disease patients enrolled from 1978 to 1988. Patients were followed for an average of 5.2 ± 2.0 years. Age-specific prevalence and incidence rates of CVA in patients with the common genotypes of sickle cell disease were determined, and the effects of hematologic and clinical events on the risk of CVA were analyzed. The highest rates of prevalence of CVA (4.01%) and incidence (0.61 per 100 patient-years) were in sickle cell anemia (SS) patients, but CVA occurred in all common genotypes. The incidence of infarctive CVA was lowest in SS patients 20 to 29 years of age and higher in children and older patients. Conversely, the incidence of hemorrhagic stroke in SS patients was highest among patients aged 20 to 29 years. Across all ages the mortality rate was 26% in the 2 weeks after hemorrhagic stroke. No deaths occurred after infarctive stroke. Risk factors for infarctive stroke included prior transient ischemic attack, low steady-state hemoglobin concentration and rate of and recent episode of acute chest syndrome, and elevated systolic blood pressure. Hemorrhagic stroke was associated with low steady-state hemoglobin and high leukocyte count.