OBJECTIVES:  Multiple sclerosis (MS) registry data and previous real world studies suggest that natalizumab treatment results in lower relapse rates compared with other disease-modifying therapies (DMTs). Relapses have also been associated with increased use of steroids and pain medication to manage symptoms. This analysis compares real-world relapse rates and symptom management between MS patients treated with natalizumab and those treated with other DMTs. METHODS:  Relapsing-remitting MS (RRMS) patients receiving a DMT for >12 months were identified from the pooled 2014–2015 Adelphi MS Disease Specific Programme, a cross-sectional study of MS patients from France, Germany, Italy, Spain, the United Kingdom, and the United States. Average treatment effects (ATEs) for 2330 patients (natalizumab, n=285; any other DMT, n=2045) were estimated and adjusted utilizing a propensity score generated from age, gender, Expanded Disability Status Scale score at current treatment initiation, line of therapy, body mass index, duration of current treatment, time since MS diagnosis, and number of comorbid conditions. Physician-reported relapses in the previous 12 months and symptom management were compared across treatments. RESULTS:  Relapse data were available for 2104 patients (natalizumab, n=249; any other DMT, n=1855), and symptom management data were available for 2330 patients (natalizumab, n=285; any other DMT, n=2045). Natalizumab-treated patients suffered fewer relapses than patients receiving any other DMT (ATE: –0.159 vs 0.507, respectively; p=0.006). The analysis of patient symptom management demonstrated that patients receiving natalizumab reported significantly less steroid use than patients receiving any other DMT (ATE: –0.019 vs 0.025, respectively; p<0.001) as well as significantly less use of drugs to manage pain symptoms than patients receiving any other DMT (ATE: –0.048 vs 0.130, respectively; p=0.036). CONCLUSIONS:  In this study, treatment with natalizumab was associated with a lower relapse rate and significantly lower requirement for symptomatic treatment compared with patients receiving any other DMT.