Objective To assess whether connective tissue disorder is evident in patients with spontaneous cervical artery dissection and therefore identify patients at risk of recurrence using a cutting-edge quantitative proteomics approach. Methods In the ReSect-study all patients with spontaneous cervical artery dissection treated at the Innsbruck University Hospital since 1996 were invited to attend a standardized clinical follow-up examination. Protein abundance in skin punch biopsies (n=50) was evaluated by a cutting-edge quantitative proteomics approach (liquid chromatography-mass spectrometry) which has hitherto not been applied to such patients. Results Patients with one-time single-vessel (n=19) or –multiple-vessel (n=13) dissections did not differ between each other or compared to healthy controls (n=12) in protein composition. Patients with recurrent spontaneous cervical artery dissection (n=6) however, showed significantly different expression of 25 proteins compared to the other groups combined. Literature review and gene ontology term annotation check revealed that 13 of the differently expressed proteins play a major role in the structural integrity of connective tissue or are linked to connective tissue disorders. These proteins showed clustering to a collagen/elastin cluster and one consisting of desmosome related proteins. Conclusion This study unravels an extracellular matrix protein signature of recurrent spontaneous cervical artery dissection. On a long run and dependent on large-scale validation, our findings may well assist in identifying patients at risk of recurrent spontaneous cervical artery dissection and thus guide therapy.