Corpus callosum (CC), the largest compact white matter fiber bundle of the human brain involved in interhemispheric transfer, is frequently damaged in the course of multiple sclerosis (MS). Cognitive impairment is one of the factors affecting quality of life of patients with benign MS (BMS). The aim of this study was to investigate the relationship between the cognitive profile of BMS patients and the extent of tissue damage in the CC. Brain conventional and DT MRI scans were acquired from 54 BMS patients and 21 healthy controls. Neuropsychological tests (NPT) exploring memory, attention, and frontal lobe cognitive domains were administered to the patients. DT tractography was used to calculate the mean diffusivity (MD) and fractional anisotropy (FA) of the CC normal appearing white matter (NAWM). An index of CC atrophy was also estimated. Nine (17%) BMS patients fulfilled criteria for cognitive impairment. Compared with controls, BMS had significantly different CC diffusivity and volumetry (P < 0.001). Compared with cognitively preserved patients, those with CI had significantly higher CC lesion volume (LV) (P = 0.02) and NAWM MD (P = 0.02). The scores obtained at PASAT were significantly correlated with CC T2 LV, and NAWM FA and MD (r values ranging from −0.31 to 0.66, P values ranging from 0.04 to <0.001). Cognitive impairment in BMS is associated with the extent of CC damage in terms of both focal lesions and diffuse fiber bundle injury. MRI assessment of topographical distribution of tissue damage may represent a rewarding strategy for understanding the subtle clinical deficits of patients with BMS. Hum Brian Mapp 2009. © 2008 Wiley-Liss, Inc.