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This preliminary study sought more information on blood oxygen level dependent (BOLD) activation, especially contralateral temporal/extratemporal spread, during continuous EEG-fMRI recordings in four patients with mesial temporal sclerosis (MTS). In two patients, EEG showed unilateral focal activity during the EEG-fMRI session concordant with the interictal focus previously identified with standard and video-poly EEG. In the other two patients EEG demonstrated a contralateral diffusion of the irritative focus. In the third patient (with the most drug-resistant form and also extratemporal clinical signs), there was an extratemporal diffusion over frontal regions, ipsilateral to the irritative focus. fMRI analysis confirmed a single activation in the mesial temporal region in two patients whose EEG showed unilateral focal activity, while it demonstrated a bilateral activation in the mesial temporal regions in the other two patients. In the third patient, fMRI demonstrated an activation in the supplementary motxor area. This study confirms the most significant activation with a high firing rate of the irritative focus, but also suggests the importance of using new techniques (such as EEG-fMRI to examine cerebral blood flow) to identify the controlateral limbic activation, and any other extratemporal activations, possible causes of drug resistance in MTS that may require a more precise pre-surgical evaluation with invasive techniques.