Background and purposeDiffusion MRI (dMRI) is sensitive to microstructural changes in white matter of people with relapse-remitting multiple sclerosis (pw-RRMS) that lead to progressive disability. The role of diffusion in assessing the efficacy of different therapies requires more investigation. This study aimed to evaluate selected dMRI metrics in normal-appearing white matter and white matter-lesion in pw-RRMS and healthy controls longitudinally and compare the effect of therapies given.Material and methodsStructural and dMRI scans were acquired from 78 pw-RRMS (29 injectables, 36 fingolimod, 13 dimethyl fumarate) and 43 HCs at baseline and 2-years follow-up. Changes in dMRI metrics and correlation with clinical parameters were evaluated.ResultsDifferences were observed in most clinical parameters between pw-RRMS and HCs at both timepoints ( p ≤ 0.01). No significant differences in average changes over time were observed for any dMRI metric between treatment groups in either tissue type. Diffusion metrics in NAWM and WML correlated negatively with most cognitive domains, while FA correlated positively at baseline but only for NAWM at follow-up ( p ≤ 0.05). FA correlated negatively with disability in NAWM and WML over time, while MD and RD correlated positively only in NAWM.ConclusionsThis is the first DTI study comparing the effect of different treatments on dMRI parameters over time in a stable cohort of pw-RRMS. The results suggest that brain microstructural changes in a stable MS cohort are similar to HCs independent of the therapies used.