Coronary optical coherence tomography (OCT) has the potential to identify in-stent neoatherosclerosis, which is a possible risk factor for late acute coronary events after drug-eluting stent implantation. The purpose of this study was to investigate differences between mid-term and late in-stent restenosis after stent implantation by quantitative and semiautomated tissue property analysis using OCT. In total, 1063 OCT image frames of 16 lesions in 15 patients were analyzed. This included 346 frames of 6 lesions in late in-stent restenosis, which was defined as restenosis that was not detected at 6 to 12 months but 12 months after follow-up coronary angiography. Signal attenuation was circumferentially analyzed using a dedicated semiautomated software. Attenuation was assessed along 200 lines delineated radially for analysis of the in-stent restenotic lesions (between the lumen and stent contours). All lines were anchored by the image wire to avoid artifacts resulting from wire location. Stronger signal attenuation at the frame level (2.46 +/- 0.78 versus 1.47 +/- 0.32, P < 0.001) and higher maximum signal intensity at the lesion level (9.19 +/- 0.19 versus 8.84 +/- 0.32, P = 0.018) were observed in late in-stent restenotic lesions than in mid-term in-stent restenotic lesions. OCT demonstrated stronger signal attenuation and higher maximum signal intensity in late in-stent restenotic lesions than in mid-term in-stent restenotic lesions, indicating the possibility of neoatherosclerosis.