BACKGROUND: Although benign multiple sclerosis (BMS) is traditionally defined by the presence of mild motor involvement decades after disease onset, symptoms of fatigue and cognitive impairment are very common. OBJECTIVE: To investigate the association between micro-structural damage in the anterior thalamic (AT) tracts and in the corpus callosum (CC), as measured by diffusion tensor imaging (DTI) tractography, and fatigue and cognitive deficits. METHODS: DTI data were acquired from 26 BMS patients and 24 sex- and age-matched healthy controls. RESULTS: General and mental fatigue scores were significantly impaired in patients compared with controls (p≤0.05 for both) and 38% of patients resulted cognitively impaired. Mean diffusivity (MD) of the AT and CC tracts was significantly higher and fractional anisotropy (FA) was lower in patients compared with controls (p<0.001 for all). Fatigue was associated with increased MD (p=0.01) of the AT tracts whereas deficit of executive functions and verbal learning were associated with decreased FA in the body (p=0.004) and genu (p=0.008) of the CC. Deficits in processing speed and attention were associated with the T2 lesion volume of the AT tracts (p<0.01 for all). DISCUSSION: These findings suggest that fatigue and cognitive impairment are quite frequent in BMS patients and are, at least in part, related to micro-structural damage and T2LV of WM tracts connecting the brain cortical and sub-cortical regions of the two hemispheres.