Kindling is an animal model of epilepsy induced by periodic focal electrical stimulation of the brain. The network of brain structures responsible for this permanent abnormal excitability is unknown. We hypothesized that the hippocampal formation serves a facilitatory role in lateral entorhinal cortex kindling. We therefore investigated the effect of dentate granule cell destruction induced by the neurotoxin, colchicine into entorhinal cortex kindling development. We found that injection of colchicine into the hippocampal formation, but not frontal cortex, resulted in a 31% increase in the number of stimulations required to establish kindling in comparison with vehicle-injected controls. The effect of intrahippocampal colchicine was due to a 95% increase in the number of stimulations required to attain a class 2 seizure. Based on these and other data, we propose that elimination of granule cells reduces activation of CA2/3 neurons, thereby impairing development of entorhinal kindling.