BACKGROUND: Neoatherosclerosis (NA) and treatment modality may influence outcomes in patients with in-stent restenosis (ISR). This study evaluated the prognostic impact of different NA patterns and percutaneous coronary intervention (PCI) strategies guided by optical coherence tomography (OCT). METHODS: We retrospectively analyzed 288 ISR lesions with OCT-defined NA treated between January 2015 and December 2023. Lesions were classified as lipidic, calcified, or mixed NA. The primary endpoint was 1-year target lesion failure (TLF), defined as a composite of cardiac death, nonfatal myocardial infarction, and clinically driven target lesion revascularization (CD-TLR). Cox regression, interaction analysis, and propensity score matching (PSM) were performed. RESULTS: No significant differences in TLF (p = 0.420) or CD-TLR (p = 0.650) were observed among NA patterns. After adjustment for clinical and procedural covariates, DES reimplantation was associated with a lower risk of TLF (hazard ratio [HR] 0.390, 95% confidence interval [CI] 0.157-0.974; p = 0.044) and CD-TLR (HR: 0.341, 95% CI: 0.114-0.925; p = 0.039) compared with DCB angioplasty. In patients with lipidic NA, a similar trend was observed (TLF: HR: 0.287; 95% CI: 0.097-0.849; p = 0.024; CD-TLR: HR: 0.171; 95% CI: 0.039-0.750; p = 0.019). However, no significant interaction was observed between the NA pattern and treatment modality (p for interaction = 0.543). CONCLUSION: No significant differences in clinical outcomes were observed across NA patterns. Although DES showed numerically favorable outcomes in lipidic NA, no significant interaction between NA pattern and treatment modality was detected. And these findings are hypothesis-generating and may relate to the additional mechanical scaffolding and plaque sealing provided by DES in lipidic NA.