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The aim of the study was to investigate the optical coherence tomography (OCT)-identified difference of in-stent restenosis (ISR) tissue characteristics between patients with and without acute coronary syndrome (ACS) at index intervention.The retrospective study included 80 patients with 85 drug-eluting stent (DES) restenosis lesions. Subjects were classified according to clinical presentation at the time of de-novo lesion intervention, namely ACS and non-ACS. OCT was performed at 5 years follow-up. The frequency of malapposition, neointimal characteristics, thrombus, and minimal stent area (MSA) were evaluated.ACS group consisted of 48 (60%) patients. The mean duration from initial intervention to OCT study was 66.15 months. Malapposition was more frequent in the ACS group (25.5% vs 2.9%, P = .006), as well as a higher prevalence of thrombus in the ACS group (21.6% vs 0%, P = .015). MSA of ACS group was significantly less than that of non-ACS group (4.99 ± 1.80 vs 5.62 ± 2.08 mm2, P = .018). Compared with non-ACS group, only MI group was related to smaller MSA (4.37 ± 1.39 vs 5.62 ± 2.08 mm2, P = .048); The unstable angina (UA) group was not associated with a decreased MSA. The occurrence of neoatherosclerosis tended to be higher in ACS group (60.8% vs 41.2%, P = .076).In DES restenosis, an ACS presentation at initial intervention is associated with a higher incidence of malapposition, thrombus, and smaller MSA.