We compared first-generation and second-generation drug-eluting stent (DES) with respect to neoatherosclerosis using optical coherence tomography or optical frequency domain imaging. In-stent restenoses in 102 first-generation and 114 second-generation DES were retrospectively assessed. Neoatherosclerosis, which was defined as the presence of lipid-laden neointima or calcification inside a stent, was observed in 33 (27.2%) and 31 (32.4%) lesions in the first-generation and second-generation DES respectively. In the first-generation DES group, the lipid length was significantly longer (5.5 ± 3.8 vs. 3.1 ± 2.1 mm, P = 0.0007), the lipid arc was significantly larger (324 ± 70° vs. 250 ± 94°, P = 0.002), the prevalence of a 360° lipid arc was significantly greater (58 vs. 31%, P = 0.03), and the fibrous cap was significantly thinner (153 ± 85 vs. 211 ± 95 µm, P = 0.02) compared with those in the second-generation DES group. These differences remained significant after adjusting for the age of the stent (lipid length: P < 0.001; lipid arc: P = 0.019; and fibrous cap thickness: P < 0.001). The proliferation course and stability of neoatherosclerosis over time might be superior in second-generation DES.