Purpose: To analyze the difference in morphological patterns between in-stent restenosis (ISR) lesions of overlapping segments and ISR lesions of non-overlapping segments with secondand third-generation drug-eluting stents (DESs) using optical frequency domain imaging (OFDI). Methods: We analyzed 23 consecutive ISR lesions after secondor third-generation DES implantation using OFDI. Results: A total of 18 men and 5 women (median age, 68.0 years; interquartile range, 51.0-74.0 years) were included in the analysis. Fourteen and nine patients underwent secondand third-generation DES implantation, respectively. The median ISR detection timepoint was 10.0 months after implantation (interquartile range, 9.0-34.0 months). In 9 out of 23 lesions, ISR was found in the stent overlap area (overlapping segment group); the remaining 14 cases were categorized as the non-overlapping segment group. In OFDI analysis, homogeneous, layered, and heterogeneous patterns were found in 22%, 55%, and 22%, respectively, of lesions in the overlapping segment group and 14%, 50%, and 35%, respectively, of lesions in the non-overlapping segment group. There was no difference in the distribution of restenotic tissue structure patterns between the groups (p = .756). Conclusions: Morphological assessments of ISR tissue using OFDI showed no difference between the overlapping and non-overlapping segment groups with second and third-generation DESs in this hypothesis generating study. (c) 2020 Elsevier Inc. All rights reserved.