Background: Delayed-release dimethyl fumarate (DMF), indicated for the treatment of patients with relapsingremitting multiple sclerosis (MS), is a disease-modifying therapy with potential immunomodulatory and neuroprotective effects. In clinical trials,DMFwasassociatedwith reduced white blood cell and absolute lymphocyte counts. CurrentUSprescribing information recommends obtaining a complete blood count, including absolute lymphocyte count (ALC), before initiating and during DMF treatment. Methods: We conducted an integrated analysis of phase 2b/3/long-term extension studies of DMF in MS (N 5 2,470) to characterize ALC profiles. Results: MeanALCsdecreasedby30%during the first year and then plateaued, remaining above the lower limit of normal (LLN). Among patients treated $6 months (N 5 2,099), 2.2% experienced ALCs ,500 mm3 persisting $6 months. ALCs remained $LLN in 84% and 76% of patients during the first 6 and 12 months, respectively; of these, 0.1% and 0%, respectively, developed ALCs ,500 mm3 persisting $6 months at any time. Evidence of ALC improvement following DMF discontinuation was observed. DMF efficacy was not substantially different in patients with and without lymphopenia. Conclusion: Lymphocyte monitoring provides effective means for early identification of patients at risk for developing severe, prolonged lymphopenia. Neurol Clin Pract 2016;6:220–229 Mellen Center for Multiple Sclerosis Treatment and Research (RJF), Cleveland Clinic, Cleveland, OH; St. Josef Hospital (AC, RG), Ruhr University, Bochum, Germany; Multiple Sclerosis Program (JTP), Baylor Institute for Immunology Research, Dallas, TX; Medical University of Lodz (KS), Lodz, Poland; and Biogen (IC, MN, JR, JLM), Cambridge, MA. Dr. Novas is currently with Alexion Pharmaceuticals, Chesire, CT; and Dr. Rana is currently with Sanofi-Genzyme, Cambridge, MA. Coinvestigators are listed at Neurology.org/cp. Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp. The Article Processing Charge was paid by the study sponsor Biogen. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercialNoDerivatives 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. Correspondence to: FOXR@ccf.org 220 © 2016 American Academy of Neurology C urrent management strategies for relapsing-remitting multiple sclerosis (RRMS) are focused on prevention of new disease activity via disease-modifying therapies (DMTs). Delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) is a DMT with potential immunomodulatory and neuroprotective effects. DMF is indicated for the treatment of patients with RRMS. In clinical trials, DMF was associated with flushing and gastrointestinal events as well as reduced white blood cell (WBC) and absolute lymphocyte counts (ALCs). Current US prescribing information recommends obtaining a complete blood count, including ALC, before initiating and during DMF treatment and considering treatment interruption in patients with ALCs ,500 mm persisting .6 months to minimize the risk of developing severe, prolonged lymphopenia and its potential complications. We conducted an integrated analysis of data from phase 2b and 3 studies of DMF to characterize ALC profiles and to examine efficacy in DMF-treated patients with and without lymphopenia.