The relation between interhippocampal seizure propagation time (IHSPT) and anatomic alterations in the human epileptic hippocampus may provide insight into the pathophysiology of temporal lobe epilepsy (TLE). Using depth electrode recordings, we measured the time required for spontaneous seizures with onset in one hippocampus to become manifest in the contralateral hippocampus in 50 patients who underwent resection of the temporal lobe of seizure origin. Cell densities in individual hippocampal subfields were determined and correlated with mean IHSPT for each patient. Mean IHSPT was significantly and inversely correlated with cell counts in CA4 only (r = -0.38, p less than 0.01, Pearson's product correlation; r = -0.52, p less than 0.001, Spearman's rank order correlation). In 5 patients with bilateral independent hippocampal seizure onset who had temporal lobectomy and a diagnosis of mesial temporal sclerosis, mean IHSPT was consistently longer from the sclerotic temporal lobe than to it. These observations suggest that anatomic changes associated with chronic epilepsy alter propagation patterns. Because CA4 is believed to modulate the output of dentate granule cells and also has commissural connections to the contralateral homotopic area, the association of decreased CA4 cells with prolongation of IHSPT suggests that the observed anatomic alterations may actively (through increased inhibition) or passively (through decreased recruitment) interfere with various routes of seizure propagation.