Serial neuroimaging studies in Alexander's disease were obtained on an African-American girl who died at 4z\x years of age. She presented with macrocephaly, psychomotor retardation, spasticity, a seizure disorder, and hydrocephalus. A thorough metabolic evaluation of defined leukodystrophies, including Krabbe's disease, adrenoleukodystrophy, metachromatic leukodystrophy, Canavan's disease, and Leigh disease, was negative. A diagnosis of Alexander's disease was made based on the clinical features and ruling out all other possible causes. It was confirmed by pathologic findings of numerous subpial, subependymal, and perivascular Rosenthal fibers throughout the entire cerebrum. Interestingly, autopsy also identified the stenotic sylvian aqueduct owing to Rosenthal fiber accumulation, explaining the origin of hydrocephalus. The evolution of magnetic resonance imaging findings appears to be unique in this disease.