In rats, most neurons in layer III of the medial entorhinal cortex are exquisitely vulnerable to prolonged seizure activity. These neurons have also been shown to die preferentially in the entorhinal cortex of patients with temporal lobe epilepsy. This lesion can be duplicated in rats by a focal injection of the indirect excitotoxin aminooxyacetic acid into the entorhinal cortex. The present study was designed to examine the neuropathological consequences of an intra-entorhinal aminooxyacetic acid injection at various time-points with a sensitive silver staining method for the visualization of damaged neurons. After 3 h, affected cells with prominently stained processes were readily observed in the transition zone of the hippocampal CA1 field and the subiculum, but no silver-stained neurons were seen in the entorhinal cortex. Less consistently, damaged neurons were observed in the presubiculum, in the temporal and perirhinal cortices and in the lateral amygdaloid nucleus. At 6 h after an aminooxyacetic acid injection, numerous silver-stained neurons, which were typically devoid of processes, were also seen in layer III of the medial entorhinal cortex. This pattern of neurodegeneration remained similar at 12 and 24 h following the aminooxyacetic acid injection, though many silver-stained neurons were noted in layer II of the lateral entorhinal cortex as well. Notably, at five days, silver-stained neurons had disappeared. Instead, dendritic arbors, debris of degenerated neurons and reactive glial cells were present in lesioned brain regions. These data demonstrate the chronology and the extent of neuronal damage following an intra-entorhinal injection of aminooxyacetic acid. The results suggest that a detailed examination of the temporal sequence of neuronal death in the entorhinal cortex and in extra-entorhinal areas is likely to benefit our understanding of the pathophysiology of temporal lobe epilepsy.