Quantified hippocampal mossy fiber synaptic reorganization and neuron losses were measured to determine the pathological features associated with epileptogenic fascia dentata. Twenty-five patients with temporal lobe epilepsy (TLE) were classified as having either mesial temporal sclerosis (MTS; 16 patients), with seizure genesis in the hippocampus, or temporal mass lesions (nine patients), with seizures that were probably extrahippocampal. Neo-Timm's histochemistry identified mossy fiber sprouting, and aberrant fascia dentata puncta densities were objectively measured by light microscopic analysis on an image-analysis computer. neuron densities determined cell losses and the two seizure groups were compared to control specimens obtained from autopsies. Results showed significantly greater fascia dentata mossy fiber puncta densities and neuron losses in TLE patients compared to autopsy specimens (p < 0.026). Furthermore, there were significant differences between the two seizure groups: 1) mossy fiber puncta densities in the inner molecular layer were significantly greater in MTS compared to lesions (p < 0.02), and 2) mossy fiber puncta densities were greater in the inner molecular layer than in the stratum granulosum in 14 of 16 MTS patients (88%) compared to four of nine patients with lesions (44%, p < 0.01). Neuron densities were significantly different comparing MTS, lesion and control groups for stratum granulosum (p = 0.0001) and Ammon's horn (p = 0.0001), with each group significantly different (p < 0.05) compared to another. All patients were either seizure-free or significantly improved 1 year or more after en bloc temporal lobectomy. There were no significant correlations between fascia dentata mossy fiber puncta densities and counts of hilar neurons, CA4 pyramids, granule cells, or years of seizures. This indicates that inner molecular layer mossy fiber puncta densities and neuron losses are greater in patients with MTS than in those with lesions, and mossy fiber sprouting probably contributes to the pathophysiology of hippocampal seizures. Furthermore, these data show that some patients with extrahippocampal lesions have mossy fiber sprouting similar to MTS patients, suggesting that hippocampi in lesion patients may be capable of epileptogenesis from synaptic reorganization.