Objective: To report the BG-12 effects on magnetization transfer ratio (MTR) in the Phase 3 DEFINE study. Background Brain MTR measurements are considered to be sensitive to changes in myelin and axonal content, with increases reflecting higher concentrations of myelin and axons. DEFINE examined MTR changes with BG-12 treatment in the magnetic resonance imaging cohort. Design/Methods: DEFINE was a randomized, double-blind, placebo-controlled study evaluating BG-12 over 2 years in relapsing-remitting multiple sclerosis (RRMS). Patients aged 18-55 years with RRMS (McDonald criteria) and an Expanded Disability Status Scale score of 0.0-5.0 were randomized 1:1:1 to placebo or BG-12 240 mg twice (BID) or three times daily (TID). MTR was analyzed in whole brain (WB) and normal-appearing brain tissue (NABT) at baseline, 1, and 2 years. Results: MTR analysis included 392 patients. In WB, mean percentage change from baseline at 2 years in median MTR was -0.386% in the placebo group versus 0.129% ( P =0.0027) and 0.096% ( P =0.0051) with BID and TID, respectively, indicating significant increases relative to placebo. In NABT, mean percentage change from baseline at 2 years in median MTR was -0.392% with placebo versus 0.190% ( P =0.0006) and 0.115% ( P =0.0029) with BG-12 BID and TID, respectively. The post hoc analysis performed on patients with no new/enlarging T2 lesions (N=147) demonstrated decreased WB MTR with placebo (mean percentage change, -0.379%), but increased WB MTR with the BG-12 BID (mean percentage change, 0.286%; P =0.0293) and TID (mean percentage change, 0.170%; P =0.0538) groups at 2 years. Likewise, MTR in NABT decreased in the placebo group (mean percentage change, -0.312%) and increased in the BID (mean percentage change, 0.314%; P =0.0285) and TID (mean percentage change, 0.171%; P =0.0644) groups at 2 years. Conclusions: DEFINE MTR results demonstrate increased brain MTR in BG-12-treated patients, potentially reflecting protective effects leading to increased myelin and axonal content. Supported by: Biogen Idec Inc. Disclosure: Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Ms. Yang has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received research support from Biogen Idec. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.