OBJECTIVE We compared intravascular ultrasound (IVUS) and 2 different generations of optical coherence tomography (OCT)-time-domain OCT (TD-OCT) and frequency-domain OCT (FD-OCT)-for the assessment of coronary disease and percutaneous coronary intervention (PCI) using stents. BACKGROUND OCT is a promising light-based intravascular imaging modality with higher resolution than IVUS. However, the paucity of data on OCT image quantification has limited its application in clinical practice. METHODS A total of 227 matched OCT and IVUS pull backs were studied. One hundred FD-OCT and IVUS pull backs in nonstented (n = 56) and stented (n = 44) vessels were compared. Additionally, 127 matched TD-OCT and IVUS images were compared in stented vessels. RESULTS FD-OCT depicted more severe native coronary disease than IVUS; minimal lumen area (MLA) was 2.33 ± 1.56 mm(2) versus 3.32 ± 1.92 mm(2), respectively (p < 0.001). Reference vessel dimensions were equivalent between FD-OCT and IVUS in both native and stented coronaries, but TD-OCT detected smaller reference lumen size compared with IVUS. Immediately post-PCI, in-stent MLAs were similar between FD-OCT and IVUS, but at follow-up, both FD-OCT and TD-OCT detected smaller MLAs than did IVUS, likely due to better detection of neointimal hyperplasia (NIH). Post-PCI malapposition and tissue prolapse were more frequently identified by FD-OCT. CONCLUSIONS FD-OCT generates similar reference lumen dimensions but higher degrees of disease severity and NIH, as well as better detection of malapposition and tissue prolapse compared with IVUS. First-generation TD-OCT was associated with smaller reference vessel dimensions compared with IVUS.