BACKGROUND: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline. METHODS: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN-alemtuzumab), followed by additional, as-needed, alemtuzumab. RESULTS: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN-alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN-alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups. CONCLUSION: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups. CLINICALTRIALSGOV IDENTIFIERS: NCT00530348; NCT00548405; NCT00930553.