Eighty-five infants ranging from 22 to 41 weeks gestation were diagnosed as having periventricular leukomalacia (PVL) using traditional neuropathologic methods. The lesions were also studied by immunocytochemistry for beta-amyloid precursor protein (beta-APP), a glycoprotein that has been observed in PVL. Using this technique, the distribution of white matter tissue necrosis was defined as focal, widespread, and diffuse. The type of PVL correlated with the gestational age at birth. The youngest infants tended to demonstrate widespread necrosis, and the oldest infants exhibited more focal necrosis. beta-APP immunopositivity was present in the axons around the foci of white matter necrosis in 76% of the patients and in the neurons of the adjacent cortex in 66% of the patients. In age-matched control patients, there was no beta-APP reactivity in the cerebral white matter or the cortex. In most patients the distribution of beta-APP-positive axons proved to be a useful marker for demonstrating the type of PVL; however, the relationship of beta-APP to the pathogenesis of PVL requires further study.