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To compare complication rates of a collagen-based vascular closure device (VCD) in patients with vs. without significant peripheral artery disease (PAD).A total of 382 patients (268 men; mean age 64.6±10.8 years) undergoing either an endovascular procedure of the lower limb (PAD group, n=132) or a percutaneous coronary intervention (PCI group, n=250) via a common femoral artery access were enrolled in this prospective study if hemostasis was achieved using the collagen-based Angio-Seal. In the PCI group, significant PAD was excluded by measurement of the ankle-brachial index. In-hospital major complications (bleeding, large hematoma, pseudoaneurysm, vessel occlusion, dissection) were recorded.Similar and low rates of major complications were observed in both arms of the study: 2 (1.5%) major complications in the PAD group and 3 (1.2%) in the PCI group (p=1.0). There was no significant difference in efficacy of the VCDs in the groups (PAD group 99.2% vs. 100% in PCI group, p=0.35).Our study shows no significant differences in the rate of major complications after utilization of a collagen-based VCD for femoral artery access site closure in patients with severe lower limb PAD compared to those without; however, complications in the PAD group tended to be more severe, with the need for surgical repair.