The aim of this study was to better understand the significance of interictal changes in water molecule diffusivity defined by diffusion-weighted imaging (DWI) in frontal lobe epilepsy (FLE), as well as to test the accuracy of interictal DWI in the definition of the epileptogenic zone (EZ). DWI was carried out in 14 patients with refractory FLE (9 negative-MRI) as well as in 25 controls. Statistical mapping analysis (SPM2) of diffusivity maps was used to detect, for each subject, significant diffusivity alterations. We then studied the relationships between diffusion and depth recorded electrical abnormalities. Clinical correlates of the extent of diffusivity changes were also tested. We found areas of significantly increased diffusivity (SID) in 13 patients. Eight had SID in the EZ, 9 within the irritative zone (IZ) and 12 outside, mainly in connected areas. We found a correlation between the extent of SID and the duration of epilepsy (p corrected=0.026, R=0.621). In addition, SID was significantly less widespread in negative-MRI patients (p=0.028). However, we found no significant differences concerning either seizure frequency (p=0.302), seizure generalization (p=0.841), history of status (p=0.396), or surgical outcome (p=0.606). We suggest that SID in normal appearing areas is not a specific signature of epileptogenicity in FLE, and is more likely to reflect multifactorial and potentially evolving neuro-glial injuries.