OBJECTIVES: To report the impact of BG-12 (dimethyl fumarate) on patient health-related quality of life (HRQoL) in CONFIRM, a 2-year, placebo-controlled study of efficacy and safety of BG-12 in patients with relapsing–remitting multiple sclerosis (RRMS). METHODS: Patients aged 18–55 years with RRMS (McDonald criteria 2005) and Expanded Disability Status Scale score 0–5.0 were randomized 1:1:1:1 to oral BG-12 240 mg twice (BID) or three times daily (TID), placebo, or subcutaneous glatiramer acetate (GA) 20 mg/day (reference comparator arm). A Short Form (SF)-36 questionnaire was administered to assess health status and HRQoL on 8 multi-item 100-point scales at baseline, 24 weeks, 1 year and 2 years. These scores were used to calculate Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. In addition, patients’ global impression of well-being was assessed at baseline and every 3 months using a 100-point visual analogue scale (VAS). Higher scores indicated better HRQoL. RESULTS: The intent-to-treat population comprised 1,417 patients. Mean PCS scores increased from baseline to 2 years with BG-12 BID (+0.49) and TID (+0.33) versus a decrease with placebo (−0.71), indicating significantly improved (BID)/a trend toward better (TID) physical health and well-being relative to placebo (p=0.0217 and p=0.0519, respectively). With GA, mean PCS score increased by 0.42 at 2 years (p=0.0259 versus placebo). SF-36 MCS scores showed similar trends but results were not statistically significant. Mean changes from baseline to 2 years in VAS scores were 0.3, −0.3 and 2.1 with BG-12 BID, TID and GA, respectively, versus −3.9 with placebo (p=0.0003, p=0.0025 and p<0.0001, respectively), indicating a significantly improved sense of well-being with active treatment. CONCLUSIONS: Together with the significant improvement in clinical and neuroradiological measures, benefits on patient-reported HRQoL further support the potential for BG-12 to become a valuable oral treatment option for patients with relapsing MS.