Introduction: In-stent restenosis (ISR) is traditionally associated with neointimal hyperplasia. However, recent studies have suggested that an underlying progression of the atherosclerotic process called neoatherosclerosis, different from intimal proliferation, could be involved in ISR development. In this study the aim was to compare the characteristics of the neoatheromatous plaque evidenced by Multislice Angio Computed Tomography, Optical Coherence Tomography (OCT) and Virtual Histology Intravascular Ultrasound (VH-IVUS) with the characteristics of de-novo lesions in native coronary vessels of patients with ISR. Material and methods: This is a prospective single-center pilot study in which patients presenting with acute chest pain and having at least one symptomatic bare-metal stent (BMS) restenosis at six months to one year after BMS implantation, were enrolled. The characteristics of the neointimal tissue developed within the implanted stents using Acio CT, OCT and VH-IVUS were studied. Results: In total, 27 patients with 38 coronary BMS were included in the study, in whom 27 ISR lesions and 43 lesions in native coronary vessels were identified. Angio CT examination revealed that atheromatous plaques responsible for ISR tend to have a larger volume compared with native lesions located in the same coronary vessel (plaque volume 91.2 mm3 for ISR vs. 60.4 mm3 for native vessels, p <0.0001). Additionally, they show more low density plaques compared to native coronary lesions located in the same coronary vessel (33.9 mm3 vs. 18.2 mm3 for the volume of the plaque with density <30 HU, p <0.0001). Plaques responsible for ISR exhibit a higher lipid content than native ones (41.1% vs. 22.9%, p = 0.05). OCT analysis indicated an irregular shaped vascular lumen in 44.4% of ISR lesions compared to 25.6% of de-novo lesions (p = 0.1). Conclusions: Neoatherosclerosis within the implanted coronary stents is associated with signs of plaque vulnerability to a significantly higher extent than the atheromatous plaques in native coronary arteries in patients with ISR presenting with an acute coronary syndrome.