Background: The treatment landscape for multiple sclerosis (MS) continues to evolve and many disease-modifying therapies (DMTs) with different routes of administration (RoA), mechanisms of action, efficacy, and safety are now approved. With this evolution, it is important to reassess and characterize real-world use of DMTs. Objectives: To describe treatment patterns and relapse rates among treatment-naïve patients with MS initiating DMT in the United States. Methods: This retrospective observational study used MarketScan Commercial Claims and Medicare data to identify treatment-naïve MS patients newly initiating DMT. Eligibility criteria were ?3 MS diagnosis claims within 1 year during the study period (January 1, 2014December 31, 2019), ?1 DMT prescription in the index period (January 1, 2015December 31, 2018), continuous medical and pharmacy enrollment, and age ?18 years. Descriptive statistics were used to compare treatment patterns and relapse rates between DMTs. Results: 5587 patients met the eligibility criteria. Mean age was 45.3 years (range 1882 years) and 72.7% were female. Initial DMT was oral in 41.3% (n=2309), injectable (INJ) in 42.2% (n=2356), and intravenous (IV) in 16.5% (n=922) of patients. Overall, patients had a mean Charlson comorbidity index score of 0.36 at baseline. IV patients were significantly more likely to use benzodiazepines and potassium channel blockers at baseline and at 12-month follow-up than patients initiating oral or INJ DMT (all p-values <0.002). At baseline, 2061 patients (36.9%) had at least one prior relapse, with 338 patients (6.0%) having two or more. Overall relapse rate at 12-month follow-up was 26.3% with mean time to first relapse of 153.9 days. More relapses were seen at baseline in IV patients than the other groups (50.1% of IV patients had ?1 prior relapse compared to 35.3% Oral patients and 33.3% INJ patients, p-value <0.001). The overall relapse rate at 12-month follow-up was also highest in IV patients (p-value = 0.003), and time to first relapse was substantially shorter (mean 136 days) than for patients initiating oral or INJ DMT (164 days and 152 days, respectively, p-value=0.008). Conclusions: Overall, patients with MS newly initiating DMT were found to have differences in baseline concomitant medications, and relapses at baseline and follow up across the routes of administration. These findings highlight how real-world MS treatment selection is individualized based on patient characteristics.