Objectives: Generalized periodic discharges (GPDs) can be observed in the electroencephalogram (EEG) of patients after acute cerebral ischemia and reflect pathological neuronal synchronization. Whether GPDs represent ictal activity, which can be treated with anti-epileptic drugs, or severe ischemic damage, in which treatment is futile, is unknown. We hypothesize that GPDs result from selective ischemic damage of glutamatergic synapses, which are known to be relatively vulnerable to effects of ischemia. Methods: We employed a macroscopic model of cortical dynamics in which we increasingly eliminated glutamatergic synapses. We compared the output of the model with clinical EEG recordings in patients showing GPDs after cardiac arrest. Results: Selective elimination of glutamatergic synapses from pyramidal cells to inhibitory interneurons led to simulated GPDs whose waveshape and frequency matched those of patients showing GPDs after cardiac arrest. Mere reduction of glutamatergic synapses between pyramidal cells themselves did not result in GPDs. Conclusions: Selective ischemic damage of glutamatergic synapses on inhibitory cortical interneurons leads to the generation of ischemia induced GPDs. Disinhibition of cortical pyramidal neurons is a candidate mechanism. Significance: This study increases the insight in the pathophysiological mechanisms underlying the generation GPDS after acute cerebral ischemia. © 2013 International Federation of Clinical Neurophysiology.