The substrates of cognitive impairment in benign MS (BMS) still need to be identified. We investigated whether cognitive impairment in BMS patients is associated with specific patterns of brain structural and functional abnormalities.Thirty-seven BMS patients (EDSS score ≤ 3.0 and disease duration ≥ 15 years) and 50 healthy controls (HC) were studied. In BMS patients, a cognitive impairment index (CII) was derived. Gray matter (GM) volumes, white matter (WM) fractional anisotropy (FA) and resting-state (RS) functional connectivity (FC) were investigated for whole-brain relevant regions (cortex, lobes, subcortical nuclei, fiber tracts) and functional networks. Univariate and multivariate analyses identified independent predictors of cognitive impairment.In BMS, median CII was 9 (IQR: 4-16). Compared to HC, BMS patients showed reduced WM FA, GM atrophy and increased RS FC in fronto-temporo-parietal regions. At multivariate analysis, percentage of T2-lesions of the corpus callosum, reduced posterior corona radiata (PCR) FA and caudate nucleus atrophy were independent predictors of worse CII. A multivariate model identified reduced PCR FA (R2 = 0.39; p = 0.001) as the only predictor of CII.Cognitive impairment in BMS is associated with structural damage of relevant brain areas. WM damage of parietal regions was the predominant predictor of worse cognitive performance in these patients.