Periventricular leukomalacia (PVL), the principal form of brain injury in the premature infant, is characterized by overt focal necrotic lesions in periventricular white matter and less prominent, more diffuse cerebral white matter injury. The early detection of the latter, diffuse component of PVL is not consistently possible with conventional brain imaging techniques. We demonstrate the early detection of the diffuse component of PVL by diffusion-weighted magnetic resonance imaging (DWI). In a premature infant with no definite cerebral abnormality detectable by cranial ultrasonography or conventional magnetic resonance imaging, DWI showed a striking bilateral decrease in water diffusion in cerebral white matter. The DWI abnormality (ie, decreased apparent diffusion coefficient) was similar to that observed with acute cerebral ischemic lesions in adults. At 10 weeks of age, conventional magnetic resonance imaging and ultrasonography showed striking changes consistent with PVL, including the presence of small cysts. The observations indicate the importance of DWI in the early identification of the diffuse component of PVL and also perhaps the role of ischemia in the pathogenesis of the lesion.