Introduction: Fingolimod (Fg), a sphingosine 1-phosphate receptor modulator, decreases the annual relapse rate (ARR) in relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to assess the efficacy and safety of Fg in daily practice in patients with RRMS, previously treated with natalizumab (Nz) or not, and systematically followed during at least 1 year. Methods: Data were collected from the patient files. Primary endpoint was the comparison between the ARR the year before Fg onset and after 1 and 2 years of Fg treatment. The secondary endpoints were the difference between Expanded Disability Status Scale (EDSS) at Fg onset and after 1 and 2 years of treatment, and safety. Results: In the whole sample, we confirmed Fg efficacy on the ARR (0.895 before vs. 0.364 1 year after, p < 0.0001). Between our two groups (with or without Nz before Fg), the ARR was higher in the Nz group during the first year but similar during the second year. The EDSS was stable during the first year of Fg but significantly higher after 2 years (3.33 vs. 3.72, p = 0.02). Concerning safety, only three patients had to discontinue Fg because of tolerance issues. Conclusion: Our study showed that Fg is safe in RRMS and can be used either after first-line treatments or after Nz. However we observed a mild disability progression after 2 years.