The membrane-bound axon guidance molecule netrin-g2 is preferentially expressed in the central nervous system and plays a role in synapse formation and maintenance. Using immunohistochemistry, immunofluorescence, and Western blotting, we investigated the possible correlation between netrin-g2 expression and intractable epilepsy (IE) using surgical samples from epilepsy patients. We used 35 samples of temporal neocortex from patients undergoing surgery for drug-refractory epilepsy and 15 autopsy samples from individuals who died in traffic accidents (i.e., samples of normal human brain). We also examined netrin-g2 expression in the hippocampus and adjacent cortex of rats with temporal lobe epilepsy (lithium chloride-pilocarpine model). Netrin-g2 was expressed in the membrane and cytoplasm of neurons from control specimens, and expression was higher in tissue from patients with intractable epilepsy. Western blotting of rat brain tissue showed that netrin-g2 was upregulated starting at 6h after kindling. Maximal expression was seen around 2 days, and relatively high expression was maintained until 30 days. Expression then returned to normal levels at 60 days, which was consistent with the immunohistochemical and immunofluorescence results. These data implicate netrin-g2 in the pathophysiology of epilepsy and are consistent with the hypothesis that this protein may participate in the abnormal development of synapses and in neuron migration.