After discontinuation of natalizumab (NAT), multiple sclerosis (MS) disease activity often recurs. We assessed the recurrence of clinical disease activity during the first year after switching from NAT to fingolimod (FTY) in patients with relapsing-remitting MS. The number of relapses and the annualized relapse rate (ARR) before, during and after NAT discontinuation were determined and compared between 26 MS patients who switched to FTY within 24 weeks, and 10 MS patients who remained without disease modifying therapy (therapy free group = TFG). Median follow-up post-NAT discontinuation was 55.1 weeks. In a subgroup (n = 20), the occurrence of contrast-enhancing-lesions (Gd+) on magnetic resonance imaging (MRI) was determined. Eleven patients (42 %) in the FTY group and seven patients (70 %) in the TFG had one or more relapses after cessation of NAT during follow-up (p < 0.05). One of the 11 (9 %) patients in the FTY group and 6/9 (67 %) patients in the TFG showed Gd+ lesions during follow-up (p < 0.05). Patients who switched to FTY ≤ 12 weeks after NAT discontinuation (n = 9) showed a trend for a lower post-NAT ARR compared to patients who started FTY therapy >12 weeks after NAT was stopped (n = 17). Most relapses in the FTY group occurred just before or within 8 weeks after starting FTY. Our observation suggests that initiation of FTY treatment after NAT discontinuation reduces the recurrence of disease activity compared to withdrawal without further immunomodulatory treatment. In the FTY group the ARR tended to depend on the time interval between discontinuation of NAT and initiation of FTY.