Rett syndrome (RS) is a clinically defined disorder which appears to be unique to females and which is associated with apparent loss of cognitive and motor skills early in life. Using the technique of gapless serial section, microscopic analysis of the brains from three cases of RS and identically processed age-matched controls was conducted to determine the nature and extent of cerebral abnormality in this disorder. Small neuronal cell size and increased cell packing density were observed throughout the brain in all three cases, without evidence of gliosis or active degeneration. These findings are consistent with a curtailment of brain development which may begin before birth. Further, the brain abnormalities in RS appear to be more diffuse than previously appreciated and are in accord with the widespread neurological symptoms characteristic of this disorder.