AIMS Recent data have reported that neoatherosclerosis could develop long after stent implantation and lead to subsequent rupture and acute coronary syndrome (ACS). We sought to identify the presence of in-stent neoatheroma (ISNA) in patients with very late stent thrombosis (VLST) using optical coherence tomography (OCT). METHODS AND RESULTS All patients from two catheterization centres who presented with ACS related to VLST underwent a standard coronary angiography and intra-coronary OCT. ISNA was defined as the combination of diffuse neointimal proliferation, lipid-laden intima with plaque organization, and fibrous cap rupture with no evidence of an uncovered strut. Out of 2139 ACS patients, 20 presented with definite VLST, including 10 with evidence of ISNA lesions, detected using OCT. The mean delay between initial percutaneous coronary intervention and VLST was longer in the ISNA patients compared with non-ISNA patients (10.5 ± 1.6 vs. 4.0 ± 0.6 years, P = 0.003). The mean LDL-cholesterol tended to be higher in ISNA patients compared with non-ISNA patients. OCT analysis revealed significantly thicker neointimal coverage as well as a lower number of uncovered struts in ISNA lesions compared with the other patients. LDL-cholesterol levels were correlated with the average neointima thickness (Spearman's rho = 0.46, P = 0.04). All the ISNA lesions were treated through initial thrombectomy followed by redo stenting in nine patients. CONCLUSION Our data show that ISNA is frequent in patients with VLST. These results suggest that OCT imaging is helpful in identifying the underlying mechanisms of VLST and, therefore, in the clinical decision-making process.