Generalized seizures during Interferon-alpha (IFN-alpha) therapy have been repeatedly described in about 1%-4% of patients. However, the mechanisms underlying IFN-alpha induced seizures are not known. We describe a patient who developed partial and secondary generalized seizures during IFN-alpha therapy while displaying a focal disruption of her blood-brain barrier (BBB) corresponding with pathological electroencephalography (EEG). To test our hypothesis that IFN-alpha induces seizure activity, we exposed rat somatosensory cortices to clinically relevant concentrations of IFN-alpha in the acute in-vitro slice preparation or in-vivo. While acute exposure did not induce epileptic activity, recordings from slices exposed to IFN-alpha in-vivo one week prior to recordings revealed pronounced epileptiform activity in > 80% of the slices. We propose that cortical exposure to IFN-alpha leads to the generation of an epileptic cortex, which explains the weeks of latency in patients from initial treatment to seizures, and stressing the importance of identifying possible BBB disruption among high-risk patients administered peripherally acting drugs.