The long-term effects of repeated brief seizures on spatial memory and hippocampal neuronal populations were assessed in kindled rats. Rats that experienced a range of 3 afterdischarges to 134 secondary generalized tonic-clonic (Class V) seizures evoked by stimulation of the olfactory bulb were evaluated in a radial arm maze task that is a measure of spatial memory and is disrupted by hippocampal damage. After completion of the memory task and a minimum of approximately 3 months after the last evoked seizure, stereological methods were used to assess neuronal populations at septal and temporal locations of the hippocampus and dentate gyrus. Repeated brief seizures induced a long-lasting deficit in spatial memory performance that was detected after a cumulative total of approximately 6 partial and 30 secondary generalized seizures. The memory deficit progressively increased as a function of the number of seizures, and was not observed in age-matched, electrode-implanted, unstimulated, but otherwise similarly handled paired controls. Neuronal loss was detected in the temporal hilus of the dentate gyrus, CA1, and CA3 of the hippocampus after 69 or more secondary generalized tonic-clonic seizures, and was associated with the progressive memory dysfunction. Repeated brief seizures induced progressive, permanent functional and structural abnormalities in the hippocampus, which included spatial memory deficits accompanied by gradually evolving neuronal loss in a pattern resembling human hippocampal sclerosis. These experimental results support the view that hippocampal sclerosis and associated memory dysfunction are induced by repeated seizures, and imply that seizure control could prevent adverse long-term consequences of seizures on hippocampal dependent functions.