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Aims: Natalizumab inhibits adherence of leukocytes to the cerebral endothelium. Leukocytes play a role in regulating the vascular tone. Natalizumab may thus also affect cerebral vasoregulation. This observational study investigates whether neurovascular coupling and cerebral autoregulation are altered after routine clinical infusion of natalizumab in patients with relapsing remitting multiple sclerosis. Methods: In eighteen patients receiving a regular infusion of 300mg natalizumab, neurovascular coupling to visual stimulation (control system approach) and dynamic cerebral autoregulation (phase and gain of 0.1Hz oscillations) were serially measured by transcranial Doppler ultrasound (before, 2 hours and 2 days after the infusion). A repeated examination 28 days after infusion served as a control situation. Results: Neurovascular coupling was altered 2 hours and 2 days after infusion with an overshooting initial hemodynamic response. After 28 days, neurovascular coupling was similar to values before the infusion. Dynamic cerebral autoregulation, cerebral blood flow velocity and pulsatility index in the middle and posterior cerebral artery were unaltered. Neurovascular coupling was not related to age, sex, disease duration, time since last relapse, clinical severity, number of previous natalizumab infusions and occurrence of new headaches after the infusion. Conclusions: Natalizumab infusion is associated with a temporarily increased initial hyperemia to functional activation. Such a hyperreactivity suggests an increased bioavailability of nitric oxide during functional activation. This is perhaps caused by altered leukocyte concentration in the cerebral microcirculation. Hemodynamic effects of immunosuppressive agents acting at the cerebral microcirculation should be considered in future research. Ideally, they could play a role in noninvasively monitoring the direct biological effects of such drugs at their site of action. A placebo-controlled trial is thus warranted to confirm the results of this observational study.