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Background Managing multiple sclerosis (MS) in cancer survivors is complex due to immune system interactions and the impact of treatment. Limited guidance exists on disease-modifying therapy (DMT) use during and after chemotherapy. This study examined how DMT decisions in breast cancer influence MS outcomes and whether chemotherapy itself affects MS disease activity.Methods Data were obtained from the MSBase registry, including 172 individuals with MS and breast cancer who received chemotherapy, and 229 for whom chemotherapy data were not available. Survival analyses assessed time to first relapse and confirmed disability progression (CDP) after cancer diagnosis, with DMT modelled as a time-varying covariate. Propensity score matching compared outcomes between those who received cancer chemotherapy adjuvant to their MS treatment and matched controls receiving standard MS treatment alone.Results Post-chemotherapy MS management varied, with most clinicians de-escalating or withholding DMTs. Older age was associated with lower relapse risk (HR = 0.90, 95% CI: 0.93–0.97, p = 0.001). Chemotherapy had a protective effect on time to first relapse (HR 0.58, 95% robust CI: 0.37 to 0.95, p = 0.03) compared to matched controls receiving standard MS treatment. Chemotherapy was not associated with a significant effect on CDP (HR 0.68, 95% robust CI: 0.38–1.23, p=0.06).Conclusion Chemotherapy was associated with better relapse outcomes compared to standard therapy in matched controls, supporting withholding or de-escalating DMTs during cancer treatment. DMT reinitiation should be guided by individual risk assessment and may be less indicated in older individuals, who demonstrated a lower relapse risk following chemotherapy.