Optical frequency domain imaging (OFDI) was utilized to compare the prevalence of neoatherosclerosis (NA) and morphological characteristics of the neointimal tissue in second generation drug eluting stent (G2-DES)-treated lesions between early (<1 year, E-ISR) and late (>1 year, L-ISR) in-stent restenotic phases. Data comparing NA and in vivo tissue characteristics between early and late in-stent restenosis (ISR) after implantation of G2-DES is limited. An OFDI analysis was performed in 50 G2-DESs {35 everolimus-eluting stent [22 cobalt-chromium (CoCr), 13 platinum-chromium (PtCr)], and 15 biolimus-eluting stent [BES]} ISR lesions (46 consecutive patients) undergoing target lesion revascularization, classified as E-ISR (n = 22 lesion) and L-ISR (n = 28 lesion). NA, defined as a neointima formation containing lipids or calcification was observed in fewer than half (24/50) of all ISR lesions with no significant difference between E-ISR and L-ISR lesions (50 vs. 46.4%, p = 0.8). There were also no significant differences in the morphological appearance and tissue characteristics between E-ISR and L-ISR lesions. ISR was more likely to occur earlier [median 8.6 (8.3-8.9) months] after PtCr-EES implantations (12 lesions vs. 1, p < 0.001), while 3/4 of the BES ISR lesions and more than 2/3 of the CoCr-EES ISR lesions were observed after 1 year of implantation [median 21.3 (20.7-27.5) months, p < 0.001]. Acknowledging some limitations, our observations may suggest that the prevalence of neoatherosclerosis and the morphological appearance, and tissue characteristics of G2-DESs restenotic lesions are similar between the early and late restenotic phases. Certain platforms (PtCr-EESs) may have preferentially presented with early ISR.