Purpose: The recent "Report of the ILAE Commission on Classification and Terminology" recommends an epilepsy classification that gives more emphasis to the underlying structural or metabolic cause rather than to the localization of the epileptogenic zone. The aim of the present study was to investigate differences in clinical features, treatment response, and prognosis in patients with mesial temporal lobe epilepsy (MTLE) caused by hippocampal sclerosis (MTLE-HS) or singular mesiotemporal cavernomas (MTLE-C) in order to evaluate the impact of underlying pathology on the course of the disease while controlling for localization. Methods: Age at onset, age at surgery, seizure frequency and semiology, pharmacoresistance, psychiatric comorbidities, memory deficits, or initial precipitating insults (e. g., febrile seizures, traumatic brain injury, infection of the central nervous system, birth complications) as well as postoperative outcome were compared in eleven patients with MTLE-C and 33 patients with MTLE-HS using nonparametric statistical methods. Key Findings: The postoperative outcome was significantly better in patients with MTLE-C, even after controlling for preoperative epilepsy duration. Patients with MTLE-HS more frequently were drug resistant (88% vs. 36%) and more often presented with an initial precipitating insult (70% vs. 27%) and with automotor seizures (79% vs. 46%). Significance: The results suggest that patients with MTLE-C show a more favorable postoperative outcome, supporting the commission's suggestion to put more emphasis on the underlying cause in future epilepsy classifications.