Diffusion-weighted images of magnetic resonance imaging, obtained by mapping apparent diffusion coefficients, are more sensitive than other magnetic resonance imaging sequences in the earliest detection of acute cytotoxic injury. The usefulness of diffusion-weighted images in focal ischemic brain injury has been documented in children and adults. We report eight full-term neonates with global cerebral hypoxic-ischemic injury and abnormalities on diffusion-weighted images. Distribution of diffusion-weighted imaging abnormalities in the eight neonates was consistent with global hypoxic-ischemic injury in full-term neonates, with diffuse cortical necrosis, border-zone infarcts, or basal ganglia/thalamic injury. Magnetic resonance imaging scans with diffusion-weighted images were obtained within the first 4 days of age in all eight neonates. In each patient, standard magnetic resonance imaging sequences substantially underestimated the extent of injury when compared with diffusion-weighted images in unmyelinated neonatal brains. Extensive injury bilaterally with basal ganglia and thalamic and widespread multifocal cortical injury correlated with a severe neurologic outcome. Lesser degrees of injury, limited to smaller sectors of cortical or border zone involvement, were associated with better neurologic outcome. The high sensitivity of diffusion-weighted images to map the extent of hypoxic-ischemic injury in neonates makes it a potentially useful tool for assessing future neuroprotective strategies for neonatal hypoxic-ischemic injury.