This report compares the relative rates and risk factors associated with stroke in adults versus children with sickle cell disease (SCD) in the United States over the last decade. We identified incident strokes in patients with SCD using ICD-9 codes for acute stroke and SCD and the California Patient Discharge Databases. We estimated SCD prevalence by using the incidence of SCD at birth with adjustment for early mortality from SCD. We identified 255 acute strokes (70 primary hemorrhagic and 185 ischemic) among 69,586 hospitalizations for SCD-related complications from 1998 to 2007. The rate of stroke in children [<18 years old (310/100,000 person-years)] was similar to young adults [18-34 years old (360/100,000 person-years)], but much higher in middle-aged [35-64 years old (1,160/100,000 person-years)] and elderly adults [> or =65 years old (4,700/100,000 person-years)]. Stroke was associated with hypertension in children and hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and renal disease in adults. Most acute strokes (75%) and in-hospital deaths from stroke (91%) occurred in adults. Our results suggest that the rate of stroke in SCD peaks in older adults and is three-fold higher than rates previously reported in African-Americans of similar age (35-64 years) without SCD. Stroke in SCD is associated with several known adult risk factors for ischemic and hemorrhagic stroke. Studies for the primary and secondary prevention of stroke in adults with SCD are urgently needed.