The fine structure of cerebral cortical synapses was investigated during failure of synaptic transmission produced by ischemia. Presynaptic and postsynaptic potentials evoked in the anterior sigmoid gyrus of the cat by stimulation of the nucleus ventralis lateralis and the DC potential between cortical layer IV and the white matter were recorded with micropipettes during cerebral ischemia produced by arterial hemorrhage in paralyzed, artificially ventilated animals. After failure of the spontaneous electrocorticogram and postsynaptic responses, the presynaptic volley failed with development of depolarization of intracortical fiber terminals and loss of axon terminal excitability. The gyrus was then biopsied and fixed in collidine-buffered OsO4. An altered pattern of distribution of synaptic vesicles was observed after presynaptic afferent fiber terminal activity was abolished by 3.5 to 4.0 minutes of cerebral ischemia. Clumping of vesicles in a region away from the cynaptic cleft was seen in about 10% of synaptic endings, and there was more than a two-fold increase in the number of presynaptic profiles devoid of vesicles in ischemic cortex.