The type of initial precipitating injury and the age at which it occurred in 20 patients with nonlesional temporal lobe epilepsy (TLE) were related to clinical features, presurgical neuroimaging, quantified hippocampal pathologies, and seizure outcomes. Clinical data, neuroimaging records, and seizure outcomes were abstracted from medical records and confirmed with patient and family contacts. Hippocampal neuron losses and mossy fiber reactive synaptogenesis were quantified independently. Results showed that the type of initial precipitating injury and the patient's age at which it occurred were related to the clinicopathological features of TLE. An initial precipitating injury occurred in 18 patients (90%), all of whom had mesial temporal sclerosis (MTS). Patients with a prolonged initial seizure or a nonseizure initial precipitating injury before age 5 years were significantly more likely to have unilateral hippocampal atrophy (p < 0.05) shown on magnetic resonance (MR) imaging, and had significantly greater inner molecular layer mossy fiber puncta densities (p < 0.001) than patients with nonprolonged childhood initial precipitating injuries and/or seizures after age 5 years. Furthermore, nonseizure injuries in patients before age 5 years had significantly longer latent periods (p < 0.05), and the patients did not respond to surgical treatment as well as other MTS patients. Those with an initial precipitating injury after age 5 years had MTS but showed significantly less inner molecular layer mossy fiber sprouting (p < 0.05) than patients whose injuries appeared before age 5 years. Patients without an initial precipitating injury (idiopathic TLE) had significantly fewer neuron losses (p < 0.05) and inner molecular layer mossy fiber puncta densities (p < 0.05) and had worse outcomes following en bloc temporal lobectomy compared to patients with MTS who had experienced initial precipitating injuries. Patients with unilateral hippocampal abnormalities on MR imaging did not show significant differences in neuron losses or aberrant mossy fiber puncta densities compared to patients without asymmetry. These results support the hypothesis that the type of initial precipitating injury and the age at which the injury occurred initiates and influences the pathophysiological process that eventually develops into MTS. These data support the notion that the pathophysiology of hippocampal damage and mossy fiber sprouting after an initial precipitating injury may be a progressive process.