✓ The sequential neuronal alterations that occur during the early phase of developing cortical infarction in the squirrel monkey were studied by light and electron microscopy. A technique used to select ischemic tissue based on spectrophotometry is described. Neuronal shrinkage, characterized by angularity, cytoplasmic eosinophilia, and nuclear pyknosis on light microscopy and by an increase in electron density of the cytoplasmic and nucleoplasmic matrix on electron microscopy, was the predominant reaction. The increased electron density of the cytoplasm and nucleoplasm suggested a diffuse alteration at the molecular level and the appearance of this abnormality between 3 and 6 hours corresponded with the development of an irreversible neurological deficit. In contrast, approximately 10% of the neurons became very swollen and pale. The pattern of perineuronal astrocytic alterations suggested that some form of interaction involving fluid transfer may exist between astrocyte and neuron and that shrinkage or swelling of neurons may depend in part upon the presence or absence of direct fluid exchange with astrocytes. Most terminal boutons became progressively shrunken and dense resembling the changes which occur in anterograde axonal degeneration. Swelling and fragmentation of large lysosomes occurred at 12 hours. Disruption of neural membranes was widespread by 24 hours and was more severe in swollen neurons.