The conventional endovascular aortic aneurysm procedure entails the placement of oversized introducer sheaths in relatively normal ileofemoral arteries to allow the delivery and deployment of endovascular prosthesis. Endoluminal manipulation with passage of oversized endoluminal devices can lead to endothelial denudation, resulting in impaired cellular function. The purpose of this study was to assess the time course of endothelial function with vasoreactivity following oversized endovascular sheath insertion ranging from 1 day to 16 weeks in normal porcine iliac arteries. Following oversized introducer sheath placement in bilateral iliac arteries, vasoreactivity was tested using both endothelium-dependent and -independent vasodilators. Intravascular ultrasonography showed a significant reduction in the luminal area at 12 and 16 weeks. This was similarly supported by morphometric analysis, which showed increased medial thickness with an elevated intima to media ratio at the same time course. Endothelium-dependent relaxation to bradykinin, calcium ionophore A23187, serotonin, and adenosine diphosphate all uniformly displayed attenuated endothelial dysfunction at all time points when compared with the control group. In contrast, endothelium-independent relaxation showed a decreased vasoresponsiveness at 4 weeks. In conclusion, this study underscored the detrimental and chronic endothelial dysfunction in a normal artery caused by oversized introducer sheath placement. Chronically impaired endothelial function may play a role leading to iliofemoral artery thrombosis or late occlusion, which were well-recognized adverse events following endovascular aneurysm procedures. Our study underscores the importance of appropriate patient selection to minimize potential sheath oversize and endograft device miniaturization to avoid vessel wall injury and maintain vasoreactivity.