Background: Neoatherosclerosis (NA) is associated with stent failure. However, systematic studies on the manifestations of NA and neovascularization (NV) at different stages after drug-eluting stent (DES) implantation are lacking. Moreover, the relationship between NA and NV in in-stent restenosis (ISR) has not been reported. This study aimed to characterize NA and NV in patients with ISR at different post-DES stages and compare the association between NA and NV in ISR lesions. Methods: A total of 227 patients with 227 lesions who underwent follow-up optical coherence tomography before percutaneous coronary intervention for DES ISR were enrolled and divided into early (E-ISR: 1 year), late (L-ISR: 1–5 years), and very-late (VL-ISR: >5 years) ISR groups. Furthermore, ISR lesions were divided into NV and non-NV groups according to the presence of NV. Results: The prevalence of NA and NV was 52.9% and 41.0%, respectively. The prevalence of lipidic NA (E-ISR, 32.7%; L-ISR, 50.0%; VL-ISR, 58.5%) and intimal NV (E-ISR, 14.5%; L-ISR, 30.8%; VL-ISR, 38.3%) increased with time after stenting. NA was higher in ISR patients with NV lesions than in those without (p 0.001). Patients with both ISR and NV had a higher incidence of macrophage infiltration, thin-cap fibroatheroma, intimal rupture, and thrombosis (p 0.01). Conclusions: Progression of lipidic NA was associated with L-ISR and VL-ISR but may not be related to calcified NA. NA was more common in ISR lesions with NV; its formation may substantially promote NA progression and plaque instability.