Endovascular repair (EVAR) has become the standard procedure in treating thoracic (TAA) or abdominal aortic aneurysms (AAA). Not entirely free of complications, a persisting perfusion of the aneurysm after EVAR, called Endoleak (EL), leads to reintervention and risk of secondary rupture. How the aortic wall responds to the implantation of a stentgraft and EL is mostly uncertain. We present a pilot study to identify peptide signatures and gain new insights in pathophysiological alterations of the aortic wall after EVAR using matrix-assisted laser desorption or ionization mass spectrometry imaging (MALDI-MSI). In course of or accompanying an open aortic repair, tissue sections from 15 patients (TAA = 5, AAA = 5, EVAR = 5) were collected. Regions of interest (tunica media and tunica adventitia) were defined and univariate (receiver operating characteristic analysis) statistical analysis for subgroup comparison was used. This proof-of-concept study demonstrates that MALDI-MSI is feasible to identify discriminatory peptide signatures separating TAA, AAA and EVAR. Decreased intensity distributions for actin, tropomyosin, and troponin after EVAR suggest impaired contractility in vascular smooth muscle cells. Furthermore, inability to provide energy caused by impaired respiratory chain function and continuous degradation of extracellular matrix components (collagen) might support aortic wall destabilization. In case of EL after EVAR, this mechanism may result in a weakened aortic wall with lacking ability to react on reinstating pulsatile blood flow.