Periventricular white matter injury, that is, periventricular leukomalacia (PVL), the dominant form of brain injury in the premature infant, is the major neuropathological substrate associated with the motor and cognitive deficits observed later in such infants. The nature of the relationship of this lesion to the subsequent cognitive deficits is unclear, but such deficits raise the possibility of cerebral cortical neuronal dysfunction. Although cortical neuronal necrosis is not a prominent feature of brain injury in premature infants, the possibility of a deleterious effect of PVL on subsequent cerebral cortical development has not been investigated. An advanced quantitative volumetric three-dimensional magnetic resonance imaging technique was used to measure brain tissue volumes at term in premature infants with earlier ultrasonographic and magnetic resonance imaging evidence of PVL (mean gestational age at birth, 28.7 +/- 2.0 weeks; n = 10), in premature infants with normal imaging studies (mean gestational age at birth, 29.0 +/- 2.1 weeks; n = 10), and in control term infants (n = 14). Premature infants with PVL had a marked reduction in cerebral cortical gray matter at term compared with either premature infants without PVL or normal term infants (mean +/- SD: PVL, 157.5 +/- 41.5 ml; no PVL, 211.7 +/- 25.4 ml; normal term, 218.8 +/- 21.3 ml). As expected, a reduction in the volume of total brain myelinated white matter was also noted (mean +/- SD: PVL, 14.5 +/- 4.6 ml; no PVL, 23.1 +/- 6.9 ml; normal term, 27.6 +/- 10.3 ml). An apparent compensatory increase in total cerebrospinal fluid volume also was found (mean +/- SD: PVL, 64.5 +/- 15.2 ml; no PVL, 52.0 +/- 24.1 ml; normal term, 32.9 +/- 13.5 ml). PVL in the premature infant is shown for the first time to be followed by impaired cerebral cortical development. These findings may provide insight into the anatomical correlate for the intellectual deficits associated with PVL in the premature infant.