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We examined the nature and extent of neuropsychologic impairment in children with sickle cell anemia (SCA) with or without stroke. Twenty-nine children with SCA received cranial magnetic resonance imaging. Strokes were classified into three groups: diffuse cortical stroke (n = 11), anterior stroke (n = 6), or none (n = 12). Children with SCA and 20 age-matched sibling control subjects then received a neurologic examination and a neuropsychologic battery of tests that included motor, verbal, spatial, attentional, and memory measures. Tests of spatial function showed that children with diffuse cortical strokes were impaired, whereas children with anterior lesions had intrusions of irrelevant material during list recall. There were no significant differences between children with stroke and sibling control subjects on motor, verbal, or memory measures. Six children had evidence of stroke on magnetic resonance imaging without any history of a damaging neurologic event. These children had impaired neuropsychologic performance relative to that of sibling control subjects in a pattern similar to that of children with overt stroke. Children with SCA without stroke did not differ from sibling control subjects on any measure. Our results indicate that overt and silent strokes result in lesion-specific neuropsychologic deficits in children with SCA.