The branching of dendrites of pyramidal neurons in premotor frontal, motor and limbic cortex have been identified by us using Golgi technique to be less in Rett Syndrome (RS) brains than in non-Rett control brains. Decreased dendritic branching per se is not pathognomonic of a particular condition and has been reported in numerous disorders associated with mental retardation. This study was designed to test whether the dendritic alterations in Rett Syndrome are the same or different from the alterations present in Down Syndrome (DS), 1 specific form of mental retardation. Sections from Brodmann's areas 6, 4, 20, 43, 28, and 17 of premotor frontal, motor cortex, inferior temporal gyrus, hippocampal formation and the striate cortex from 16 Rett brains, 9 non-Rett brains and 9 Down's brains were prepared for dendrite analysis using the rapid Golgi technique. Drawings of apical and basilar dendrites of pyramidal neurons from 2 cortical layers and Cal were submitted to Sholl analysis. The analyses of Rett brains were compared with the analyses of the Trisomy 21 brains using the repeated measures analysis of covariance, with age as a covariate. The studies demonstrate in our sample that basal dendrites of layer III and V of frontal, layer IV of subiculum, and layer V of motor cortex and apical dendrites of layer III of frontal cortex have a significantly reduced dendritic arborization in RS compared with Trisomy 21. This study suggests that the cortical distribution of the dendritic alterations is specific for Rett Syndrome, and that the premotor frontal, motor and subicular cortex are preferentially involved in the, as yet, undefined process which affects brain growth and function in RS.