Background: Ofatumumab has demonstrated superior efficacy and favorable safety for up to 2.5 years versus teriflunomide in relapsing multiple sclerosis (RMS)., Objective: Further characterize efficacy and safety of ofatumumab in RMS., Methods: Efficacy set: patients randomized to ofatumumab/teriflunomide in ASCLEPIOS I/II (core). Safety set: patients who received ⩾ 1 dose of ofatumumab in ASCLEPIOS I/II, APLIOS, APOLITOS (all core), or ALITHIOS (umbrella open-label extension). Patients received continuous ofatumumab or were newly switched from teriflunomide. Data cut-off: 25 September 2021., Results: In the efficacy set ( n = 1882), the continuous ofatumumab group had a low annualized relapse rate (ARR 0.05 (95% confidence interval: 0.04-0.07)), low numbers of gadolinium-enhancing (Gd+) T1 lesions (0.01 lesions/scan) and fewer new/enlarging T2 lesions (annualized rate 0.08). Overall, 78.8% met three-parameter "no evidence of disease activity" criteria through 4 years. Switching from teriflunomide led to reduced ARR, risk of confirmed disability worsening (CDW), new/enlarging T2 lesions, Gd+ T1 lesions, and serum neurofilament light chain. In the continuous and newly switched ofatumumab groups, cumulative 3- and 6-month CDW rates remained low. In the safety set ( n = 1969), the most frequently reported adverse events were infections and infestations (58.35%). No new safety signals were identified., Conclusion: Ofatumumab has a favorable longer-term benefit-risk profile in RMS., Trial Registry: ALITHIOS (NCT03650114): https://clinicaltrials.gov/ct2/show/NCT03650114., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All support for the present manuscript (e.g. funding, provision of study materials, medical writing, article processing charges) and the studies were sponsored and funded by Novartis Pharma AG, Basel, Switzerland. Novartis Pharma AG supported the development of this manuscript, provided data analyses according to the direction of the authors, and provided funding for medical writing support. Open access fee was paid by Novartis. Medical writing support for the development of this publication, under the direction of the authors, was provided by James Currie (BSc, Hons; PhD.), Laura Crocker (BMedSci, Hons), and Philippa Lloyd (BSc, Hons) of Ashfield MedComms, an Inizio company, and was funded by Novartis Pharma AG. Stephen L Hauser currently serves on the scientific advisory board of ACCURE, Alector, Annexon, board of directors of Neurona, and has previously consulted for BD, Moderna, and NGM Bio. Dr Hauser also has received travel reimbursement and writing support from F. Hoffmann-La Roche and Novartis AG for anti-CD20-therapy-related meetings and presentations. Grants: NIH/NINDS (R35NS111644) and Valhalla Foundation; within the past 36 months, no longer active: National Multiple Sclerosis Society (RR 2005-A-13). Ronald Zielman is a full-time employee of Novartis. Ayan Das Gupta is a paid and permanent employee of Novartis. Jing Xi is an employee of Novartis. Dee Stoneman is a full-time employee of Novartis. Goeril Karlsson is a full-time salaried employee of Novartis. Derrick Robertson declares grants or contracts from Anokion, Atara Biotherapeutics, Biogen, GW Pharmaceuticals, Novartis, PRIME CME, TG Therapeutics, CorEvitas, EMD Serono, Genentech, Janssen, PCORI and Sanofi; consulting fees from Biogen, Genentech, EMD Serono, Janssen, Bristol Myers Squibb, Horizon, Novartis, Sanofi, TG Therapeutics, Alexion, Greenwich Biosciences and Mallinckrodt; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biogen, EMD Serono, Genentech, TG Therapeutics, Bristol Myers Squibb, Janssen, PRIME CME, Sanofi, Alexion and Horizon. Jeffrey A Cohen declares consulting fees from Biogen, Convelo, EMD Serono, Gaossamer Gio, Mylan and PSA; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for ACTRIMS; other financial or non-financial interests for Sage—serving as an Editor of Mult Scler J. Ludwig Kappos declares grants or contracts from any entity (payments made to institution) from Novartis, Roche, and Innosuisse; consulting fees (payments made to institution) from AurigaVision AG, Bayer AG, df-mp Molnia & Pohlman, Genentech, Glaxo Smith Kline, Janssen LLC, Japan Tobacco Inc., Merck, Novartis, Roche, Senda Biosciences Inc., Shionogi BV, Wellmera AG; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (payments made to institution) from BMS, Celgene, Janssen Pharmaceuticals, Merck, Novartis and Roche; support for attending meetings and/or travel (payments made to institution) from MH Consulting, Österreichische Gesellschaft für Neurologie, Novartis Biocieˆncias S.A. and Eli Lilly; participation on a Data Safety Monitoring Board or Advisory Board (AB, payments made to institution) from Actelion, Merck Healthcare KGaA, Novartis, Roche, Sanofi and TG Therapeutics and (DSMB, payments made to institution) from Minoryx Therapeutics S.L. and Santhera Pharmaceuticals; leadership or fiduciary role in other board, society, committee or advocacy group paid or unpaid from Neurostatus-UHB AG—Supervisory Board (unpaid), payment to institution; (charitable) Foundation Clinical Neuroimmunology and Neuroscience Basel (“RC2NB”)—CEO (employment by University Hospital Basel); MAGNBIMS Steering Committee, EUROPEAN CHARCOT FOUNDATION (Board membership)—no payment.