<i>Background:</i> An underlying extracellular matrix defect is suspected in patients with spontaneous cervical artery dissection (SCAD). We test the hypothesis that levels of matrix metalloproteinase (MMP) 2 and 9, and elastase, extracellular-matrix-regulating enzymes involved in the vascular wall remodeling process, are modified in SCAD. <i>Methods:</i> The authors prospectively and consecutively recruited 47 patients with SCAD and 52 patients with an ischemic stroke from another cause in 2 centers, and measured their plasmatic level of MMP-2, MMP-9 and elastase 3 months after the vascular event. <i>Results:</i> Patients with SCAD had a higher mean MMP-2 level compared with controls [379.2 (SD = 76.6) vs. 355.9 (75.1) ng/ml; p = 0.11] and had more frequently a high level of MMP-2 (>326 ng/ml) than controls (77.8 vs. 54.5%, p = 0.019). This association was stronger in patients with multiple dissection than single artery dissection or controls (84.6, 75.0 and 54.5%, respectively, p = 0.018). The levels of MMP-9 and elastase were similar in cases and controls, but more patients had a high level of these enzymes in the group with multiple dissections than in the group with single artery dissection or controls. <i>Conclusion:</i> Patients with SCAD have higher plasma levels of proteases, particularly MMP-2. The association is stronger in patients with multiple dissections.