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Background and Purpose: Carotid artery stenosis is a major risk factor for ischemic stroke. Despite carotid artery stenting, in-stent restenosis (ISR) remains challenging. Pigs serve as an ideal ISR model. This study aims to establish a novel porcine model of carotid ISR using open-loop and closed-loop stents and to assess ISR with optical coherence tomography (OCT) and histopathology, comparing incidence and vascular response between stent types., Methods: Twelve adult male Bama miniature pigs underwent carotid stenting with either open-loop or closed-loop stents. The animals received antiplatelet therapy pre- and postimplantation. Postimplantation evaluations at 90 days included carotid digital subtraction angiography (DSA), OCT, histopathological examination, and electron microscopy., Results: Both stent types showed ISR as detected by OCT and DSA. OCT revealed comparable neointimal proliferation within stent struts for both types, with no significant differences in stent, lumen, and neointimal dimensions. Histopathological analysis and electron microscopy provided insights into tissue responses and healing processes following stent implantation. No significant difference in ISR incidence was found between the stent types based on a χ 2 test (p = .110). OCT and hematoxylin-eosin staining exhibit the highest consistency in evaluating neointimal area., Conclusions: The novel porcine ISR model demonstrated similar ISR outcomes for open-loop and closed-loop stents. OCT proved to be a highly consistent and valuable tool for evaluating stent and arterial conditions, comparable to histopathological findings. However, due to a small sample size, the validity of these preliminary findings requires further investigation to be confirmed., (© 2024 The Author(s). Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)