BACKGROUND: Fingolimod can lead to increased risk of cardiac events such as bradycardia or atrioventricular (AV) block. OBJECTIVE: Evaluate acute and long-term effects of fingolimod on heart rhythm (HR), heart rate variability (HRV) and development of AV-blocks. METHODS: In 64 patients with relapsing-remitting multiple sclerosis Holter ECG monitoring (HEM) and HRV analysis were performed 24h before, six h during and 72h after initiation of fingolimod. We additionally analyzed a 24h HEM after a follow up of >/= three months. RESULTS: Heart rate (HR) decreased significantly (p < 0.001) under fingolimod treatment with nadir at five hours after starting and maintained decreased for 72h. Five (7.8%) patients suffered from new-onset AV-block requiring cessation of treatment. In four of five patients (80%), the AV-block could only be documented in the 72h-HEM with a median time of occurrence at 14h. The mean heart rate was still significant lower after a mean follow up time of 14.1 +/- 9.6 months (85.0 +/- 9.8 vs. 75.3 +/- 16.2 bpm; p = 0.002) in comparison to baseline. CONCLUSION: The treatment with fingolimod leads to an increase of vagal activation which persists even after 14 months of treatment. These changes did not return to baseline levels on treatment with fingolimod. Based on our data an additional at least 24h hour-HEM after the initiation of fingolimod therapy should be considered.