© 2018 Associazione Italiana di Fisica Medica Purpose: NODDI (Neurite Orientation Dispersion and Density Imaging) and DTI (Diffusion tensor imaging) may be useful in identifying abnormal regions in patients with MRI-negative refractory epilepsy. The aim of this study was to determine whether NODDI and DTI maps including neurite density (ND), orientation dispersion index (ODI), mean diffusivity (MD) and fractional anisotropy (FA) can detect structural abnormalities in cortical and subcortical gray matter (GM) in these patients. The correlation between these parameters and clinical characteristics of the disease was also investigated. Methods: NODDI and DTI maps of 17 patients were obtained and checked visually. Region of interest (ROI) was drawn on suspected areas and contralateral regions in cortex. Contrast-to-noise ratio (CNR) was determined for each region. Furthermore volumetric data and mean values of ND, ODI, FA and MD of subcortical GM structures were calculated in both of the patients and controls. Finally, the correlations of these parameters in the subcortical with age of onset and duration of epilepsy were investigated. Results: Cortical abnormalities on ODI images were observed in eight patients qualitatively. CNR of ODI was significantly greater than FA and MD. The subcortical changes including decrease of FA and ND and increase of ODI in left nucleus accumbens and increase of the volume in right amygdala were detected in the patients. Conclusions: The results revealed that NODDI can improve detection of microstructural changes in cortical and subcortical GM in patients with MRI negative epilepsy.