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Background: Cytomegalovirus (CMV) is the major infectious cause of congenital abnormalities in the central nervous system due to intrauterine infection in humans. Design and population: Twenty-seven fetuses with congenital CMV infection documented at 20–21 weeks' gestation by invasive prenatal diagnosis (amniotic fluid culture and PCR positive with a viral load > 10 5 copies/ml) underwent histological examination. We focused our attention on brain and placenta to understand the histopathogenesis of cerebral damage and to find a possible correlation between placental infection and ischemic brain damage. Material and methods: Fetal sections were studied with haematoxylin and eosin staining, immunohistochemistry for CMV early (ppUL44) and leukocyte common antigen CD45 to detect the inflammatory cells. Results: CMV-positivity was detected in all placentas and 55% (15/27) of brains. Six out of 15 CMV-positive brains showed mild inflammatory response without necrosis and only mild telencephalic leukencephalopathy. Four out of 15 CMV-positive brains showed a moderate CD45-positive inflammatory response associated with focal microglial nodules and telencephalic leukencephalopathy. The CD45-positive inflammatory response in the remaining five of the 15 CMV-positive brains was severe and associated with diffuse cerebral damage such as cortical necrosis, polymicrogyria and periventricular leukomalacia. No damage was observed in CMV-negative brains. Conclusions: Diffuse chronic villitis with necrosis was found in all the placentas of fetuses with severe brain damage. In other placentas, chronic villitis and necrosis were only focal. Brain damage may be caused not only by CMV infection but also by inflammatory infiltration and hypoxia due to severe placentitis.