Objective: Teriflunomide is a once-daily, oral disease-modifying therapy (DMT) for relapsing forms of multiple sclerosis (MS). We studied clinical outcomes in a real-world setting involving a population-based large cohort of unselected patients enrolled in The Danish Multiple Sclerosis Registry (DMSR) who started teriflunomide treatment between 2013-2019., Methods: This was a complete nationwide population-based cohort study with prospectively enrolled unselected cases. Demographic and disease-specific patient parameters related to treatment history, efficacy outcomes, and discontinuation and switching rates among other clinical variables were assessed at baseline and during follow-up visits., Results: A total of 3239 patients (65.4% female) started treatment with teriflunomide during the study period, 56% of whom were treatment-naïve. Compared to previously treated patients, treatment-naïve patients were older on average at disease onset, had a shorter disease duration, a lower Expanded Disability Status Scale score at teriflunomide treatment start and more frequently experienced a relapse in the 12 months prior to teriflunomide initiation. In the 3001 patients initiating teriflunomide treatment at least 12 months before the cut-off date, 72.7% were still on treatment one year after treatment start. Discontinuations in the first year were due mainly to adverse events (15.6%). Over the full follow-up period, 47.5% of patients discontinued teriflunomide treatment. Sixty-three percent of the patients treated with teriflunomide for 5 years were relapse-free, while significantly more treatment-naïve versus previously treated patients experienced a relapse during the follow-up (p<0.0001). Furthermore, 85% of the patients with available data were free of disability worsening at the end of follow-up., Conclusions: Solid efficacy and treatment persistence data consistent with other real-world studies were obtained over the treatment period. Treatment outcomes in this real-world scenario of the population-based cohort support previous findings that teriflunomide is an effective and generally well-tolerated DMT for relapsing MS patients with mild to moderate disease activity., Competing Interests: This study was funded by Sanofi. VP: has received support for scientific meetings from Merck and Sanofi Genzyme and honoraria for lecturing from Alexion. MDB: None. VS: None. PVR: has served on scientific advisory board for Biogen, Sanofi, Roche, Novartis, Merck, and Alexion, has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, has received support for congress participation from Biogen, Genzyme, Roche, Merck, Novartis. ZI: has served on scientific advisory boards, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, Merck, Roche, Sanofi Genzyme. MK: None. CH: has served on scientific advisory board for Biogen, Sanofi, Roche, Novartis, has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, has received support for congress participation from Biogen and Roche. ZM: None. HR: None. TS: has served on scientific advisory boards, received support for congress participation, received speaker honoraria and received research support from Biogen and Novartis, and received support for congress participation by Roche. AW: has served on scientific advisory board for Merck, Biogen and Roche, has received honoraria for lecturing and publications from Sanofi Genzyme, Merck, Roche and has received support for congress participation from Biogen, Genzyme, Teva, Merck and Roche. JvW and SSG are employees of Sanofi. SB: has received support for congress participation from Biogen and Roche. FS: has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, EMD Serono, Merck, Novartis, Roche, Sanofi Genzyme and Teva. MM: has served on scientific advisory board for Biogen, Sanofi, Roche, Novartis, Merck, Abbvie, Alexion has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, has received research support and support for congress participation from Biogen, Genzyme, Roche, Merck, Novartis. The specific roles of these authors are articulated in the ‘author contributions’ section. With reference to PLOS ONE policies on sharing data and materials, we confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials.