Abstract: Objective: We aimed to investigate patterns of electroencephalography-correlated functional MRI (EEG-fMRI) and subtle structural abnormalities in patients with mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (MTLE-HS) or normal MRI (MTLE-NL). Methods: We evaluated EEG-fMRI acquisition of the 25 patients with diagnosis of MTLE who had interictal epileptiform discharges (IEDs) in the intra-MRI EEG: 13 MTLE-HS and 12 MTLE-NL. fMRI was performed using echo-planar images in a 3T MRI coupled with EEG acquired with 64 MRI-compatible electrodes. In the first level analyses, the time of the IEDs ipsilateral to the epileptogenic zone was used as the paradigm, and four contrasts maps were built according to the variation of the hemodynamic response function (HRF) peaks (0, + 3, + 5, and + 7 s). Second level group analyses were performed combining the contrast maps of MTLE-HS or MTLE-NL patients with each different HRF obtained at the first level. Areas of gray matter atrophy were evaluated with voxel-based morphometry (VBM) in both groups. Results: MTLE-HS and MTLE-NL had IED-related positive BOLD (posBOLD) detected in the ipsilateral anterior temporal lobe and insula. However, only MTLE-HS had significant posBOLD on contralateral hippocampus and anterior cingulate, whereas MTLE-NL had areas of posBOLD on ipsilateral frontal lobe. Both groups had significant IED-related negBOLD responses in areas of the default mode network (DMN), such as posterior cingulate and precuneus. There was no overlap of both posBOLD and negBOLD and areas of atrophy detected by VBM. Significance: Similar IEDs have different patterns of hemodynamic responses in subgroups of MTLE. In both MTLE-HS and MTLE-NL, there is a possible suppression of the DMN related to IEDs, as demonstrated by the negBOLD in these areas. The brain areas involved in the interictal related hemodynamic network are not the regions with the most significant gray matter atrophy in MTLE with or without MRI signs of HS Ver menos