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Abstract Background Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system with an increasing worldwide prevalence. Since 1993, more than 15 disease-modifying immunotherapies (DMTs) have been licenced and have shown moderate efficacy in clinical trials. Based on the heterogeneity of the disease and the partial effectiveness of therapies, a personalised medicine approach would be valuable taking individual prognosis and suitability of a chosen therapy into account to gain the best possible treatment effect. The primary objective of this review is to assess the differential treatment effects of all approved DMTs in subgroups of adults with clinically isolated syndrome or relapsing forms of MS. We will analyse possible treatment effect modifiers (TEM) defined by baseline demographic characteristics (gender, age), and diagnostic (i.e. MRI measures) and clinical (i.e. relapses, disability level) measures of MS disease activity. Methods We will include all published and accessible unpublished primary and secondary analyses of randomised controlled trials (RCTs) with a follow-up of at least 12 months investigating the efficacy of at least one approved DMT, with placebo or other approved DMTs as control intervention(s) in subgroups of trial participants. As the primary outcome, we will address disability as defined by the Expanded Disability Status Scale or multiple sclerosis functional composite scores followed by relapse frequency, quality of life measures, and side effects. MRI data will be analysed as secondary outcomes. MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL and major trial registers will be searched for suitable studies. Titles and abstracts and full texts will be screened by two persons independently using Covidence. The risk of bias will be analysed based on the Cochrane “Risk of Bias 2” tool, and the certainty of evidence will be assessed using GRADE. Treatment effects will be reported as rate ratio or odds ratio. Primary analyses will follow the intention-to-treat principle. Meta-analyses will be carried out using random-effects models. Discussion Given that individual patient data from clinical studies are often not available, the review will allow to analyse the evidence on TEM in MS immunotherapy and thus support clinical decision making in individual cases. Systematic review registration PROSPERO CRD42021279665 .