Background.—Modification of migraine-associated cerebrovascular reactivity may provide insight into the mechanism of action of a given therapeutic intervention. Methods.—With transcranial Doppler and a breath-holding index, cerebrovascular reactivity to hypercapnia was evaluated in 20 patients with migraine without aura interictally and in 11 healthy controls. Patients were started on prophylactic treatment with flunarizine 10 mg per day, and measurements were repeated at the end of every month for 3 months. Headache status was evaluated clinically via a headache index. Headache index; breath-holding index; systolic, diastolic, and mean blood flow velocities; and pulsatility index measurements were recorded at every session. Results.—The baseline breath-holding index was significantly higher in the migraine group compared to the control group (P = .002). No difference in other parameters was found between the groups. The change in the headache index was significant (P<.001), indicating a beneficial effect from flunarizine. The breath-holding index improved significantly after treatment (P<.001), and the baseline difference in the breath-holding index between the pretreatment migraine group and the control group was no longer evident at 3 months. There was no significant change with treatment in the other transcranial Doppler parameters. Conclusion.—Our finding of unchanged blood flow velocities but normalized cerebrovascular reactivity after treatment suggests that the mechanism of action of flunarizine in migraine does not involve a vasodilatory effect on cerebral vessels. It may be instead that flunarizine modifies cerebrovascular reactivity through its action on centrally located structures that subserve autonomic vascular control.