One possible explanation for the mismatch between tissue damage and preservation of neurological functions in patients with benign multiple sclerosis (BMS) is that the pathophysiology differs from that occurring in other multiple sclerosis (MS) phenotypes. The objective of this study was to identify pathologically specific patterns of tissue integrity/damage characteristics of patients with BMS, and markers of potential prognostic value. The pyramidal system was investigated in 10 BMS patients and 20 controls using voxel-based morphometry to assess grey matter (GM) atrophy, and diffusion tractography and quantitative magnetization transfer to quantify the microstructural damage in the corticospinal tracts (CSTs). Widespread reductions in GM volume were found in patients compared with controls, including the primary motor cortex. A significant decrease was observed in the mean macromolecular pool ratio (F) of both CSTs, with no fractional anisotropy (FA) change. GM volume of the primary motor areas was associated with clinical scores but not with the CST parameters. The mismatch between F and FA suggests the presence of extensive demyelination in the CSTs of patients with BMS, in the absence of axonal damage. The lack of correlation with GM volume indicates a complex interaction between disruptive and reparative mechanisms in BMS.