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Background Patients aged ≥35 years at multiple sclerosis (MS) onset with an Expanded Disability Status Scale (EDSS) ≥3 in the first year are at highest risk of aggressive MS (EDSS ≥6 within 10 years). Those without these features are at lowest risk. We aimed to assess whether high-efficacy therapy improves outcomes in high-risk patients and whether its benefit varies by MS severity.Methods This longitudinal cohort study analysed MSBase and OFSEP registry data. Patients were categorized into high- or low-risk of aggressive MS. Within each risk strata, relapse and disability accumulation were compared between those receiving high-efficacy therapy (fingolimod, cladribine, monoclonal antibodies) vs. other/no therapy. Marginal structural models, adjusting for demographics, MS course, relapses, disability, and MRI activity, were used to evaluate treatment effects and interaction with aggressive MS risk.Results 4560 patients (893 high risk, 3667 low risk) were studied. Continuous treatment with high-efficacy therapy vs other/no therapy reduced the risk of relapse and disability accumulation in patients at both high-risk and low-risk of aggressive MS.There was no evidence of an interaction between aggressive MS risk and treatment strategy. The risk of relapse was lowest in patients at low-risk of aggressive MS treated with high-efficacy therapy (HR0.58, 95%CI 0.54–0.62). High-efficacy therapy reduced the risk of disability accumulation across both aggressive MS risk strata.Conclusion High-efficacy therapy reduces relapse and disability accumulation in patients at both high- and low-risk of aggressive MS, with no differential treatment benefit. These findings support widespread use of high-efficacy therapy in relapsing MS.