To investigate whether multiple sclerosis (MS) tissue damage is associated with the presence and severity of fatigue, we obtained magnetization transfer (MT) and diffusion tensor (DT) magnetic resonance imaging from 28 patients with MS (14 with and 14 without fatigue). MT ratio and mean diffusivity did not differ between fatigued and non-fatigued MS patients. No correlation was found between Fatigue Severity Scale scores and any of the MT and DT MRI-derived quantities. This preliminary study suggests that the severity of overall MS pathology in the brain seems not to be a critical factor contributing to the development of fatigue in MS.