OBJECTIVES: As the number of available disease-modifying therapies (DMT) for relapsing-remitting multiple sclerosis (RRMS) expands, consideration of all evidence on comparative efficacy of newer second generation therapies with established first generation therapies is required to inform clinical care and health policy.  This network meta-analysis (NMA) estimates the relative efficacy of DMT in reducing relapses and slowing short-term progression of disability in RRMS. METHODS: A systematic review of RCTs of interferon-beta, glatiramer acetate (first generation DMTs), natalizumab, alemtuzumab, fingolimod, teriflunomide, laquinimod, and BG-12 (second generation DMTs) compared with each other or with placebo for the treatment of RRMS, identified 20 eligible RCTs  (n=14610).  A random-effects NMA model was used to calculate relative annualized relapse rate (ARR) and hazard ratio (HR) of short-term disability progression. RESULTS: Statistically significant reductions in ARR versus placebo, between 24% - 69% for second generation DMTs and 16% - 33% for first generation DMTs were found.  Alemtuzumab, natalizumab, fingolimod, and BG-12 were significantly more efficacious than other DMTs in reducing ARR.  There was greater uncertainty associated with DMT efficacy in reducing short-term disability progression.  Significant improvements over placebo in reducing short-term disability progression were restricted to second generation DMTs alemtuzumab, natalizumab, fingolimod, laquinimod, BG-12, and teriflunomide 14mg (HR 0.27 - 0.54). No statistically significant improvements in short-term disability progression were exhibited by first generation DMTs and teriflunomide 7mg. CONCLUSIONS: The growing number of innovative second generation DMTs offers the potential of therapeutic advances in reducing relapse rates in RRMS, with less certain benefits on short-term disability progression.  Despite these potential advantages, the relative position of second generation DMTs on the RRMS treatment landscape remains to be defined, due to potentially serious side effects, limited long-term safety data and their high cost.