Although the use of drug-eluting stents (DES) has dramatically decreased the incidence of in-stent restenosis (ISR), concerns regarding the late manifestations of ISR remain. Optical coherence tomography (OCT) imaging provides unique insights into characteristics and patterns of ISR. We report a case of late DES ISR with unusual heterogeneous intracoronary luminal characteristics suggestive of vulnerable atherosclerotic plaque activity by OCT imaging. This case demonstrates that late ISR after DES may involve more than mere neointimal hyperplasia with lesion-associated craters, septae, and neoatherosclerosis. The use of OCT provides novel insights into the mechanisms and potential biology of the late DES ISR.