BACKGROUND AND OBJECTIVE: High-efficacy (HE) disease-modifying therapies (DMT) are increasingly used to treat multiple sclerosis (MS). Concerns arise when considering the decreasing efficacy and increasing risk of adverse events in aging patients. We aimed to describe disease activity and treatment trajectories in patients with MS who de-escalated from an HE DMT to an moderate-efficacy (ME) DMT. METHODS: We performed a cohort study based on data from the Danish Multiple Sclerosis Registry (DMSR) including patients with relapsing-remitting MS (RRMS), who switched from an HE DMT to an ME DMT as defined by Danish authorities. We included patients from October 2007 to July 2023. Median follow-up time was 0.8 years (IQR 0.3-2.5). RESULTS: In total 333 patients (76.0% females, mean age: 45.1 years) de-escalated for various reasons. Most patients de-escalated from natalizumab or fingolimod (43.8% and 42.0%, respectively) to dimethyl fumarate (47.5%). At 2 years after de-escalation, the cumulative risk of relapse was 38% (95% CI 31-44) and 53% (95% CI 46-60) for inflammatory disease activity (relapses and/or radiological disease activity). Age (HR 0.96, 95% CI 0.94-0.98) and inflammatory disease activity prior to de-escalation (HR 2.05, 95% CI 1.45-2.91) were associated with inflammatory disease activity post de-escalation. DISCUSSION: De-escalation from primarily natalizumab and fingolimod did not effectively ensure disease stability in this cohort. Younger age and inflammatory disease activity prior to de-escalation were risk factors for inflammatory disease activity post de-escalation, which can help guide future studies on de-escalation.