The prophylactic effect of metoprolol in the treatment of migraine is well known, but its mode of action is still unclear. In the past, increased CO2 reactivity has been reported as one pathognomic finding in interictal migraineurs. Using transcranial Doppler we assessed CO2 reactivity in 20 migraineurs before and 3 h after the first intake of 50 mg metoprolol, and subsequently twice after 1 and 8 weeks of continuous therapy with 150 mg metoprolol/d. Before initiation of therapy, migraineurs as a group had increased CO2 reactivity (p=0.07) compared to 20 age- and sex-matched volunteers. While treatment with metoprolol has been reported to affect amplitudes of increased contingent negative variation or visual evoked potentials in interictal migraineurs, it had no influence on enhanced CO2 reactivity in the present study. Moreover, the pretreatment value of CO2 reactivity did not correlate with the clinical efficacy of metoprolol after a 2-month treatment period.