Serial sections of cortical resection of 30 patients suffering from drug-resistant epilepsy were processed for parvalbumin and calbindin-D28k immunocytochemistry to determine local circuit neuron populations. Our findings indicate that there is not a simple mechanism to explain neocortical epileptic foci. On the basis of the present results it can be suggested that: (1) reduced percentage of local circuit neurons in the vicinity of neoplasms may account for a decreased intracortical inhibition. (2) Abnormal morphology and distribution of local circuit neurons may result in abnormal cortical inhibition in patients with focal cortical dysplasia, and, probably, in other focal migrational disorders, including neuronal nests in the white matter. (3) Increased percentages of immunoreactive local circuit neurons and fibers in focal neocortical necrosis (cavernous angiomas), diffuse hypoxic encephalopathy, and hippocampus in patients with temporal lobe epilepsy due to mesial sclerosis, may play a role in epilepsy. These neurons can be activated by reduced excitatory inputs, or they may establish abnormal synaptic contacts with other inhibitory neurons. (4) Lack of consistent morphologic abnormalities in the neocortex of patients with temporal lobe epilepsy, and in patients with cryptogenetic frontal lobe epilepsy, suggests that electrically abnormal neocortical foci in these cases are probably epiphenomena.