Abstract Background To examine whether past and current reserve-related activities make the brain less susceptible to MS pathology (i.e., lesions or disease-related atrophy). Methods This secondary analysis of a cohort study included 276 healthy controls (HC), and 65 clinically isolated syndrome (CIS), 352 relapsing-remitting MS (RR) and 109 secondary- progressive MS (SPMS) patients. Past reserve-related activities comprised educational and occupational attainment. Current reserve-related activities comprised strenuous and non-strenuous activities. MRI was performed on 3Â T scanner. Regression and non-parametric analysis examined relationships between MRI metrics and reserve-related activities. Results Multivariate models (HC as referent) revealed significant interactions in predicting strenuous reserve-related activities with chronic lesion burden (for CIS), brain- (for RR & SPMS), subcortical- (for CIS, RR, & SPMS) and amygdala- (for RR) volumes. Maximal Lifetime Brain Growth was higher for RR patients who engaged in running before and after diagnosis, rather than only before or never. Residual Brain Volume was higher in RR patients who did weights-exercise before and after diagnosis, as compared to only before. Conclusions Reserve-related activities are related to brain health cross-sectionally in all MS subgroups, and longitudinally in RR patients. Consistent with reserve theory, RR patients who maintained strenuous activities had higher Maximal Lifetime Brain Growth and Residual Brain Volume. The studyâ s limitations are discussed, including the potential for recall bias and design limitations that preclude causal inference.