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Background In the treatment of relapsing-remitting multiple sclerosis (RRMS), de-escalation—defined here as switching to a lower-efficacy therapy—is often considered by both patients and physicians. However, evidence to guide these decisions remains limited. We aimed to compare clinical outcomes between patients who de-escalated therapy versus those who continued their therapy.Method In this retrospective analysis of data from an observational, longitudinal cohort of 87,239 MS patients from 186 centers across 43 countries, we matched treatment episodes of adult RRMS patients who underwent treatment de-escalation from either high- to medium-, high- to low-, or medium to low-efficacy therapy, with counterparts that continued their treatment, using propensity score matching, incorporating 11 variables. Relapses and 6-month confirmed disability worsening were assessed using proportional and cumulative hazard models.Results Matching resulted in 876 pairs (de-escalators: 73% females, median [interquartile range] age 40.2 years [33.6, 48.8], Expanded Disability Status Scale [EDSS] 2.5 [1.5, 4.0]; non-de-escalators: 73% females, age 40.8 years [35.5, 47.9], EDSS 2.5 [1.5, 4.0]), with median follow-up of 4.8 years. Patients who underwent de-escalation faced an increased hazard of future relapses (Hazard ratio 2.36, 95%-CI [1.79–3.11], p<0.001), which was confirmed when considering recurrent relapses (2.43 [1.97–3.00], p<0.001). It was also consistent across subgroups stratified by age, sex, disability, disease duration and time since last relapse.Conclusion/Discussion De-escalation cannot be recommend as a universal treatment strategy in RRMS. The decision to de-escalate should be considered on an individual basis, as its safety is not clearly guided by specific patient or disease characteristics.