BACKGROUND: There are few reports about the differences between drug-eluting stents (DES) and bare metal stents (BMS) in neoatherosclerosis associated with in-stent restenosis (ISR), so we compared the frequency and characteristics of neoatherosclerosis with ISR evaluated by optical coherence tomography (OCT) in the present study. METHODS AND RESULTS: Between March 2009 and November 2016, 98 consecutive patients with ISR who underwent diagnostic OCT were enrolled: 34 patients had a BMS, 34 had a 1st-generation DES, and 30 had a 2nd-generation DES. Neoatherosclerosis was defined as a lipid neointima (including a thin-cap fibroatheroma [TCFA] neointima, defined as a fibroatheroma with a fibrous cap <65 µm) or calcified neointima. As a result, lipid neointima, TCFA neointima and calcified neointima were detected in 39.8%, 14.3%, and 5.1%, respectively, of all patients. The frequency of neoatherosclerosis was significantly greater with DES than BMS (48.4% vs. 23.5%, P=0.018). The minimum fibrous cap thickness was significantly thicker with DES than BMS (110.3±41.1 µm vs. 62.5±17.1 µm, P<0.001). In addition, longitudinal extension of neoatherosclerosis in the stented segment was less with DES than BMS (20.2±15.1% vs. 71.8±27.1%, respectively, P=0.001). CONCLUSIONS: OCT imaging demonstrated that neoatherosclerosis with ISR was more frequent with DES than BMS and its pattern exhibited a more focal and thick fibrous cap as compared with BMS.