OBJECTIVE Cortical spreading depression and neurogenic inflammation have been hypothesized to be key steps in the development of migraine headache. Recent studies have highlighted matrix metalloproteinase-9 (MMP-9) in cortical spreading depression, neurogenic inflammation, and cerebral ischemia. To seek their possible association, we investigated plasma MMP-9 levels in migraineurs during headache-free periods. METHODS Plasma MMP-9 levels in 84 migraine subjects and 61 controls were determined by enzyme-linked immunosorbent assay. In addition, 23 patients with tension type headache were included in the study as comparative subjects. RESULTS The MMP-9 levels in migraineurs (42.5+/-4.6 ng/mL, mean+/-SE) were significantly higher than those in controls (25.4+/-2.7 ng/mL, P< .005). Those levels in tension type headache subjects (24.6+/-4.8 ng/mL) did not differ from those in controls. There was no significant difference between subjects having migraine with aura and those without aura. The MMP-9 levels did not correlate with age, duration of illness, frequency of migraine attack, duration of headache attack, or medication for headache. Mean plasma MMP-9 levels were the highest in subjects from whom blood samples were taken 2-4 days after their latest attack. CONCLUSIONS The degradation of extracellular matrix showing the increase of MMP-9 in migraineurs may be associated with an abnormality in their blood vessel permeability. MPP-9 plays some role in migraine pathophysiology. Further studies of MMPs are necessary to elucidate their role.