The aim of this study was to explore the relationship between in-stent neoatherosclerosis (ISNA) and the neutrophil-to-lymphocyte ratio (NLR) in patients with in-stent restenosis (ISR) following drug-eluting stent (DES) implantation. We divided 216 patients into 3 groups based on the NLR tertile. We performed a comparative analysis of baseline, angiographic, and features of optical coherence tomography (OCT) between the NLR groups and performed univariate and multivariate logistic regression analyses to assess the association of the NLR with ISNA and in-stent thin-cap fibroatheroma (TCFA). Patients in the third tertile NLR group had a higher incidence of ISNA and in-stent TCFA compared with those in the first tertile. Multivariate logistic regression analysis showed that the hazard ratios and 95% confidence intervals for ISNA and TCFA were 2.673 (1.257-5.684; P = 0.038) and 4.272 (1.740-10.488; P = 0.004), respectively, for patients in the highest tertile compared with those in the lowest tertile. Our study showed that an increased NLR was associated with ISNA and in-stent plaque fragility in patients with ISR following DES implantation.