In the present study, we adopted a novel method-local diffusion homogeneity (LDH)-to characterize the structure feature in mesial temporal lobe epilepsy (MTLE). Diffusion-weighted images were acquired from 11 left MTLE patients, 16 right MTLE patients, and 20 healthy controls from May 2014 to January 2015. Local diffusion homogeneity was compared among patient groups and controls by 2 sample t test. The discriminative value of LDH abnormalities was examined by receiver operating characteristic (ROC) curve analysis. Correlations with disease duration and onset age in both patient groups were assessed using Pearson's coefficient. Both patient groups exhibited lower LDH in the anterior corpus callosum (P < 0.05, corrected), and this regional anomaly exhibited excellent classification performance in left MTLE patients (sensitivity = 82%, specificity = 100%), right MTLE patients (sensitivity = 81%, specificity = 90%), and the entire patient cohort (sensitivity = 82%, specificity = 95%). In summary, left and right MTLE patients show common pathological changes in the anterior corpus callosum. This regional LDH abnormality is a potential quantitative biomarker for MTLE.