Introduction: The objective of the present study was to evaluate the effectiveness and safety of teriflunomide in relapsing–remitting multiple sclerosis (RRMS) patients treated in a real-world setting. Methods: This retrospective study was conducted at neurology departments of 15 hospitals in 2 Spanish Autonomous Regions. The primary endpoint was annualized relapse rate (ARR) during teriflunomide treatment. Secondary endpoints included changes in Expanded Disability Status Scale (EDSS), radiological activity, and adverse events (AEs). Results: 485 patients (72.2% women, mean of 36.5 years) were included; 74.8% had previously received other disease-modifying treatment. EDSS score at inclusion was 2.0. Mean time receiving teriflunomide was 2.5 years. The ARR during teriflunomide treatment was 0.16, a 20% lower than at baseline (0.20), although the difference did not reach statistical significance (P = 0.098). The mean number of relapses significantly decreased after teriflunomide initiation, with 0.17 relapses at month 12, 0.11 at month 24, and 0.13 at month 36, compared to 0.50 in the year before teriflunomide initiation (P