Summary Objective Temporal and extratemporal white matter abnormalities have been identified frequently in patients with refractory mesial temporal lobe epilepsy (rMTLE). However, the identification of potential water diffusion abnormalities in patients with drug‐responsive, benign MTLE (bMTLE) is still missing. The aim of this study was to identify markers of refractoriness in MTLE. Methods The study group included 48 patients with bMTLE (mean age 42.8 + 13.5 years), 38 with rMTLE (mean age 41.7 + 14.1 years) and 54 healthy volunteers. Diffusion tensor imaging (DTI) was performed to measure mean diffusivity (MD) and fractional anisotropy (FA) in a regions‐of‐interest analysis comprising hippocampi and temporal lobe gray and white matter regions. The presence of hippocampal sclerosis (Hs) was assessed using automated magnetic resonance imaging (MRI) evaluation. For statistics we used chi‐square test; two‐tailed, two‐sample t‐test; and stratified linear regression. Results The significant demographic differences between the two patient groups were sex (p = 0.003), duration of epilepsy (p = 0.003) and complex febrile convulsions (p = 0.0001). In rMTLE, temporal white matter MD was higher and FA lower, as compared to bMTLE. The analysis of diagnostic accuracy (area under the receiver operator characteristic ROC curve AUC) showed that FA had an AUC for discriminating patients affected from those unaffected by refractory MTLE of 74.0% (p < 0.001), a value that was higher than that of temporal MD (64.0%), hippocampus volume (65.0%), and Hs (66.0%). Significance We performed DTI measurements in MTLE and found a significant reduction of FA along the white matter of the temporal lobes in rMTLE, suggesting it as a valuable measure of refractoriness in MTLE.