We compared efficacy and treatment persistence in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS) initiating natalizumab compared with interferon-? (IFN-?)/glatiramer acetate (GA) therapies, using propensity score-matched cohorts from observational multiple sclerosis registries.The study population initiated IFN-?/GA in the MSBase Registry or natalizumab in the Tysabri Observational Program, had ?3 months of on-treatment follow-up, and had active RRMS, defined as ?1 gadolinium-enhancing lesion on cerebral MRI at baseline or ?1 relapse within the 12 months prior to baseline. Baseline demographics and disease characteristics were balanced between propensity-matched groups. Annualized relapse rate (ARR), time to first relapse, treatment persistence, and disability outcomes were compared between matched treatment arms in the total population (n = 366/group) and subgroups with higher baseline disease activity.First-line natalizumab was associated with a 68% relative reduction in ARR from a mean (SD) of 0.63 (0.92) on IFN-?/GA to 0.20 (0.63) (p [signed-rank] <0.0001), a 64% reduction in the rate of first relapse (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.28-0.47; p <0.001), and a 27% reduction in the rate of discontinuation (HR 0.73, 95% CI 0.58-0.93; p = 0.01), compared with first-line IFN-?/GA therapy. Confirmed disability progression and area under the Expanded Disability Status Scale-time curve analyses were not significant. Similar relapse and treatment persistence results were observed in each of the higher disease activity subgroups.This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse and treatment persistence outcomes compared to first-line IFN-?/GA. This needs to be balanced against the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients.This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse rates and treatment persistence outcomes compared to first-line IFN-?/GA.