OBJECTIVES: To report the impact of BG-12 (dimethyl fumarate) on patient health-related quality of life (HRQoL) in DEFINE, a 2-year, randomized, double-blind, placebo-controlled, multicentre study of the efficacy and safety of BG-12 in patients with relapsing–remitting multiple sclerosis (RRMS). METHODS: Patients aged 18–55 years with RRMS (McDonald criteria) and an Expanded Disability Status Scale (EDSS) score of 0–5.0 were randomized 1:1:1 to placebo or oral BG-12 240 mg twice (BID) or three times daily (TID). 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; higher scores indicated better HRQoL. These scores were used to calculate the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. RESULTS: Overall, 1,234 patients were enrolled and treated. Mean baseline PCS and MCS scores decreased with increasing disability (EDSS score). Mean SF-36 PCS scores increased from baseline to 2 years with BG-12 BID (+0.45) and TID (+0.51) versus a decrease with placebo (−1.36; both p<0.001), indicating an improvement in physical health and well-being. Similar trends were observed on SF-36 MCS scores (BG-12 BID [+0.20] and TID [+1.05] versus placebo [−1.06]; p=0.065 and p<0.002, respectively). Most individual domain scores revealed a significant treatment effect for BG-12 BID at 6, 12, and 24 months. The proportion of patients who achieved clinically important improvements in PCS and MCS scores (≥5-point change) was significantly higher in the BG-12 groups versus placebo (all p<0.05). CONCLUSIONS: Together with the significant effects on clinical endpoints (reduced proportion of patients relapsed, annualized relapse rate, and disability progression) and magnetic resonance imaging measures of disease activity, the demonstrated benefits on patient-reported HRQoL further supports a potential role for BG-12 as a valuable oral treatment option in patients with relapsing MS.