Although Fingolimod is registered as a second-line drug in relapsing-remittend multiple sclerosis (RRMS) in Europe there are no clinical studies available comparing Fingolimod (FTY) and Natalizumab (N). This observational cohort-study used health data routinely collected in outpatient neurology practices throughout Germany completing a treatment period of 12 months included 237 patients starting on N and 190 patients on FTY because of failure of the first-line treatment. Mean relapse rate drastically decreased in both treatment groups within three months of therapy in a similar degree and remained on a low level. Both treatment groups saw a similar proportion of patients with unchanged and improved EDSS (80.53 % in FTY, 79.32 % in N). There was no statistically significant difference between the proportion of patients being relapse free (75.79 % in FTY, 71.73 % in N), progression free (87.39 % in FTY, 82.70 % in N) or relapse and progression free (71.05 % in FTY, 62.03 % in N) at 12 months in both strata. Clinical efficacy of FTY and N in RRMS second-line-therapy was similar during the first 12 months of treatment.