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<h4>Background and aims</h4>The prognosis of stented lesions differs according to in-stent neointimal characteristics on optical coherence tomography (OCT). In particular, patients who show in-stent heterogeneous neointima are associated with a higher incidence of target lesion revascularization (TLR) compared with those who show in-stent non-heterogeneous neointima. However, the relationship between in-stent neointimal characteristics and native coronary atherosclerosis progression has not been clearly elucidated. The study aimed to investigate the relationship between in-stent neointimal characteristics and progression of native atherosclerosis.<h4>Methods</h4>The neointimal characteristics of 377 patients with 377 drug-eluting stents (DESs) were quantitatively and qualitatively assessed using OCT. The OCT-based neointima was categorized as homogeneous (n = 207), heterogeneous (n = 93), and layered (n = 77). The relationship of non-target lesion revascularization (non-TLR) with neointimal characteristics was evaluated after OCT examination of the stents.<h4>Results</h4>After a median follow-up duration of 40.0 months, patients with heterogeneous neointima showed significantly higher non-TLR rates than those with homogeneous neointima and tended to have higher non-TLR rates than those with layered neointima (heterogeneous vs. homogeneous:14.0% vs. 8.7%, p = 0.046; heterogeneous vs. layered neointima:14.0% vs. 7.8%, p = 0.152). Multivariate analysis showed that the independent determinants for non-TLR were heterogeneous neointima (HR: 2.237, 95% CI: 1.023-4.890, p = 0.044) and chronic kidney disease (hazard ratio [HR]: 8.730, 95% CI: 2.175-35.036, p = 0.002).<h4>Conclusions</h4>The heterogeneous neointima in DES-treated lesions was associated with a higher incidence of non-TLR and target lesion failure. This finding suggests that the neointimal pattern may reflect the progression of the native lesion.