Background: Fingolimod slows heart rate (HR) due to vagomimetic effects and might cause additional cardiovascular autonomic changes. While the time course of HR changes is well described, the extent and course of cardiovascular autonomic changes upon fingolimod initiation has not yet been evaluated. This study, therefore, intended to assess cardiovascular autonomic changes during the first 6 h after fingolimod initiation. Methods: In 21 patients with relapsing-remitting multiple sclerosis (RRMS), we recorded respiration (RESP), electrocardiographic RR interval (RRI), systolic and diastolic blood pressure (BPsys, BPdia) at rest, before and 0.5, 1, 2, 3, 4, 5, and 6 h after fingolimod initiation. We calculated parameters of total autonomic modulation [RRI standard deviation (RRI-SD), RRI coefficient of variation (RRI-CV), RRI-total powers], mainly sympathetic cardiac modulation [RRI low frequency (LF) powers], sympathetic BP modulation (BPsys-LF powers), parasympathetic modulation [square root of the mean squared difference of successive RRIs (RMSSD), RRI high frequency (HF) powers], sympatho-vagal cardiac balance (RRI-LF/HF ratios), and baroreflex sensitivity (BRS). We compared parameters between the eight measurements [analysis of variance (ANOVA) or Friedman test with post-hoc analysis; significance: p < 0.05]. Results: After fingolimod initiation, RESP, BPsys, and BPsys-LF powers remained unchanged while RRIs, RRI-CV, RRI-SD, RRI-total powers, RRI-LF powers, RMSSD, RRI-HF powers, and BRS increased after 1 h and rose to peak values occurring after 5, 1, 2, 2, 1, 4, 4, and 4 h, respectively. After 3 h, BPdia had decreased significantly and was lowest after 5 h. RRI-LF/HF ratios decreased to a nadir after 4 h. Conclusions: The increases in parasympathetic and overall cardiac autonomic modulation and in BRS seen with fingolimod initiation are theoretically beneficial for the MS patient's cardiovascular system. However, long-term studies must show whether these effects persist or are attenuated (e.g. due to S1P1 receptor down-regulation upon continued fingolimod therapy).