Seven girls with Rett syndrome, a progressive degenerative encephalopathy affecting girls, were studied with single photon emission computed tomography and compared with an aged-matched control group of nine normal children. Global cerebral blood flow was significantly lower in Rett syndrome (54 vs 69 mL/100 g per minute), and the flows in prefrontal and temporoparietal association regions of the telencephalon were markedly reduced, whereas the primary sensorimotor regions were relatively spared. The flow distribution in Rett syndrome is very similar to the distribution of brain metabolic activity in infants of a few months of age. The abnormal regional cerebral blood flow distribution most likely reflects the widespread functional disturbances in the brain of patients with Rett syndrome, whereas computed tomographic and neuropathologic examination only reveal slight changes when compared with normal children.