Background and Purpose-Observations in patients with arterial aneurysms, fi bromuscular dysplasia, and spontaneous cervical artery dissection (sCAD) indicat e that protease inhibitor deficiency might boost the enzymatic destruction of ar terial tissue and increase the risk of these arterial wall diseases. Here we pre sent the first large investigation of the protease inhibitor hypothesis in patie nts with sCAD. Methods -Eighty patients with sCAD were compared with 80 age- and sex-matched healthy individuals, α 1-antitrypsin (α 1)and α 2-macro globulin (α 2-MG) levels, and α 1-AT genotypes were assessed and compared between groups. Results -α 1-AT and a2-MG levels as well as α 1 genotype s did not differ significantly between patients and controls. The frequency of Z alleles in the patient group was higher than in the control group and than in o ther cohorts from Europe; however, the difference remained nonsignificant. All p atients with Z alleles had internal carotid artery dissections. Conclusions -O verall, this data does not support the hypothesis that protease inhibitor levels or α 1 genotypes play an important role in the etiology of sCAD. The present d ata does not exclude that the Pi-Z allele might have an influence on subgroups of sCAD, such as internal carotid artery dissections. Background and Purpose-Observations in patients with arterial aneurysms, fi bromuscular dysplasia, and spontaneous cervical artery dissection (sCAD) indicat e that protease inhibitor deficiency might boost the enzymatic destruction of ar terial tissue and increase the risk of these arterial wall diseases. Here we pre sent the first large investigation of the protease inhibitor hypothesis in patients with sCAD. Methods-Eyeight patients with sCAD were compared with 80 age- and sex-matched healthy individuals, α 1-antitrypsin (α 1) and α 2-macro globulin (α 2-MG) levels, and α 1-AT genotypes were assessed and compared between groups. Results -α 1-AT and a2-MG levels as well as α 1 genotypes did not differ significantly between patients and controls. The frequency of Z alleles in the patient group was higher than in the control group and than in o ther cohorts from Europe; however, the difference remains nonsignificant. All p atients with Z alleles had internal carotid artery diss ections. Conclusions -O verall, this data does not support the hypothesis that protease inhibitor levels or α 1 genotypes play an important role in the etiology of sCAD. The present d ata does not exclude that the Pi-Z allele might have an influence on subgroups of sCAD, such as internal carotid artery dissections.