Objective The first data on the effect of presence of patent foramen ovale (PFO) with high-volume right-to-left shunt (RLS) on cerebral vasomotor reactivity (CVMR) in migraineurs are herein presented. In addition, the immediate effect of air microbubbles on CVMR has been determined. Methods Breath-holding index (BHI) and percent velocity decrease during hyperventilation (HPV) tests were performed before and after agitated saline injections in bilateral middle and posterior cerebral arteries (MCA and PCA) in 38 migraineurs (19 with aura) and 18 control subjects. Results Presence of PFO correlated with a significant decrease of MCA BHI (1.43 +/- 0.39 vs 1.04 +/- 0.67, p = 0.032) and marginal reduction of PCA BHI (1.25 +/- 0.46 vs. 1.01 +/- 0.39, p = 0.090) in migraineurs. After agitated saline injection, PCA BHI significantly decreased from 1.03 to 0.78 (p = 0.007) in patients with PFO, from 1.15 to 0.91 (p = 0.014) in those without PFO, and from 1.01 to 0.76 (p = 0.023) in subjects with migraine and PFO. No significant MCA BHI difference was noted soon after bubble injection. Conclusions The presence of high grade RLS is associated with reduced vasodilatory CVMR in migraineurs. Further decrease of CVMR of PCA upon aerogenic microemboli passage may support the mechanism of 'facilitation with subclinical cerebral ischemia caused by microembolism', hypothesis explaining the onset of migraine.