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Background/Objectives There is a need for clinically translatable MRI biomarkers of multiple sclerosis (MS) disability outcomes, particularly progression independent of relapse activity (PIRA). We examined the association between cross-sectional brain and lesion volume measures and disability outcomes, including PIRA.Methods From the international MSBase registry, we retrospectively recruited 1598 patients with relapsing-remitting MS, a suitable MRI brain scan and at least three EDSS scores and one year follow-up from the MRI-linked clinical visit. MRI analysis was performed using icobrain ms. Predictors of interest included normalised whole brain volume (WBV), grey matter volume (GMV) and lateral ventricular volume (LVV). Associations between these measures and time to PIRA, confirmed disability worsening (CDW), secondary progressive MS and confirmed disability improvement (CDI) were examined with multivariable Cox regression models.Results Median follow-up was 7.8 years (IQR: 4.9–9.6) and 69.6% of participants received high-efficacy disease-modifying therapy during follow-up. Baseline LVV was a significant predictor of time to PIRA (HR 1.008 [95% CI: 1.002–1.013, p = 0.005]) and all other disability outcomes. WBV was a significant predictor of time to CDW (HR 0.997 [95% CI: 0.995–0.998, p < 0.001]) and CDI (HR 1.008 [95% CI: 1.005–1.012, p < 0.001]), whilst GMV predicted CDI (HR 1.009 [95% CI: 1.005–1.014, p < 0.001]).Conclusion Our results provide additional, real-world evidence that cross-sectional MRI measures of neurodegeneration are relevant to MS disability outcomes in the modern treatment era. LVV appears to be a particularly robust marker of brain volume and predictor of important MS disability outcomes, including PIRA.