Purpose: To evaluate evolution and elucidate clinical phenotypes related to prognosis of patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) treated exclusively with antiepileptic drugs (AED). Methods: Forty-seven out of 68 MTLE-HS patients treated between January 2005 and June 2010 were retrospectively studied for demographic, clinical and outcome data. The population was divided into drug-responder and drug-resistant patients; the latter was divided, according to the duration of the seizure-free periods along their evolution, into patients with at least one seizure-free period longer than one year and those with shorter periods. Variables were compared between drug-responders vs drug-resistants and drug-resistants with long seizure-free periods vs drug-resistants without it. Results: There were 7 (15%) drug-responders, 39 (83%) drug-resistants and 1 patient (2%) with an undetermined response. Eighteen (46%) drug-resistant individuals had seizure-free periods longer than one year, with mean duration of 46 months (3.8 years). Since no factor was statistically associated with long seizure-free period within drug-resistants, we can clinically distinguish two phenotypes: women with left HS and late onset of seizures, with poor prognosis, and men with right HS and earlier appearance of seizures, attaining a better outcome. Twenty out of 47 (42.5%) patients followed an intermittent pattern of epilepsy. Conclusions: Non-surgical MTLE-HS drug-resistant patients can achieve long seizure-free periods with AED, but relapses are common. Female gender, left or bilateral lesion and later onset of seizures seem to be bad prognosis factors within MTLE-HS drug-resistant patients. (C) 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.