Acute and recovery brain biopsies of three patients with Reye's Disease are described. Pleomorphic changes of neuronal mitochondria were identified in all of the acute biopsies, similar in appearance to the characteristic alterations of hepatic mitochondria. Distinctive myelin bleb formation may be directly attributable to the mitochondrial injury. The mitochondrial lesion is reversible. There is morphologic evidence for regeneration and repair of myelin; but the presence of myelin ovoids at long intervals after recovery indicates a loss of some myelinated fibers. The neuronal mitochondrial changes, pleomorphism with matrix expansion, and myelin bleb formation, reflect a specific biochemical injury which is characteristic of Reye's Disease. Other and more severe changes may be attributable to ischemic injury secondary to brain edema.