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Background Clinical guidelines for relapsing remitting multiple sclerosis (RRMS) do not recommend disease modifying therapy (DMT) escalation after a single on-treatment clinically silent MRI lesion (CSL).Methods From the MSBase international registry, we studied adults with RRMS who had MRI brain scans 6-18 months apart while clinically stable and established on a DMT. Cox models compared outcomes (relapse and 6 month confirmed disability worsening [CDW]) in those with and without CSLs, adjusted for sex, age, calendar year, MS duration, EDSS score, relapses in the prior 2 years, DMT efficacy and country health expenditure. In those with CSLs on platform or moderate-efficacy DMTs, an emulated a target trial compared DMT escalation within 6 months of a silent lesion versus unchanged DMT (unless a post-MRI clinical event occurred).Results Among 10,308 people with RRMS, 2-year hazard ratios (HR [95% confidence interval]) comparing CSL with no CSL were 1.78 [1.59–2.00] for relapse and 1.38 [1.18–1.61] for CDW. Associations were similar in people with both single and multiple CSLs, on platform and moderate-efficacy baseline DMTs, and regardless of disease duration. In 2,295 people with CSLs on platform and moderate-efficacy DMTs, DMT escalation (n=288) reduced the median 4-year relapse risk from 38.9% to 17.0% (HR 0.34 [0.23–0.48]).Conclusions People with RRMS with single or multiple on-treatment clinically silent MRI lesions have higher subsequent risks of relapse and disability worsening than those without CSLs. DMT escalation mitigates the relapse risk. Contrary to clinical guidelines, DMT escalation should be considered even after a single CSL.cyrus.daruwalla@nhs.net