OBJECTIVE:To evaluate 5-year efficacy and safety of alemtuzumab in treatment-naive patients with active relapsing-remitting MS (RRMS) (CARE-MS I; NCT00530348). METHODS:Alemtuzumab-treated patients received treatment courses at baseline and 12 months later; after the core study, they could enter an extension (NCT00930553) with as-needed alemtuzumab retreatment for relapse or MRI activity. Assessments included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale EDSS score increase ≥1.5 if baseline EDSS = 0), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease baseline score ≥2.0), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs). RESULTS:Most alemtuzumab-treated patients (95.1%) completing CARE-MS I enrolled in the extension; 68.5% received no additional alemtuzumab treatment. ARR remained low in years 3, 4, and 5 (0.19, 0.14, and 0.15). Over years 0–5, 79.7% were free of 6-month CDW; 33.4% achieved 6-month CDI. Most patients (61.7%, 60.2%, and 62.4%) had NEDA in years 3, 4, and 5. Median yearly BVL improved over years 2–4, remaining low in year 5 (years 1–5−0.59%, −0.25%, −0.19%, −0.15%, and −0.20%). Exposure-adjusted incidence rates of most AEs declined in the extension relative to the core study. Thyroid disorder incidences peaked at year 3 and subsequently declined. CONCLUSIONS:Based on these data, alemtuzumab provides durable efficacy through 5 years in the absence of continuous treatment, with most patients not receiving additional courses. CLINICALTRIALS.GOV IDENTIFIER:NCT00530348; NCT00930553. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that alemtuzumab durably improves efficacy outcomes and slows BVL in patients with RRMS.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.