Continuous subdural electrocorticographic (ECoG) monitoring was performed to test the hypothesis that human temporal lobe epileptogenicity, during long-term monitoring following antiepileptic drug (AED) withdrawal, regardless of the specific AED regimen, is dependent upon ECoG ictal onset and interhemispheric spread of epileptic activity. In 121 patients, ECoG parameters were analyzed for association with seizure frequency, a clinical measure of epileptogenicity. Significantly associated with increased seizure frequency were: ictal medial temporal lobe onset, absence of ictal frontal lobe desynchronization and short interhemispheric propagation time (IHPT). Seizure frequency during long-term ECoG monitoring was not predictive of post-operative seizure outcome. It is concluded that, following AED withdrawal, regardless of the specific AED regimen, increased seizure frequency is associated with medial temporal lobe ictal onset, short IHPT and absence of frontal lobe desynchronization. The results confirm the hypothesis that human temporal lobe epileptogenicity, after withdrawal, is dependent upon ECoG ictal onset and interhemispheric spread of epileptic activity. Future development of procedures which promote ECoG factors associated with increased seizure frequency following AED withdrawal might decrease duration of invasive long-term monitoring and improve efficiency for the pre-surgical selection of temporal lobectomy candidates. Intervention producing ictal frontal lobe desynchronization and increased IHPT might inhibit temporal lobe epileptogenicity and should be evaluated for therapeutic efficacy outside of the long-term monitoring context.