The impact of contrast type on coronary optical coherence tomography (OCT) imaging has received limited research. We conducted a blinded, prospective, single-center, randomized, controlled crossover study comparing iso-osmolar contrast media (IOCM) with low-osmolar contrast media (LOCM) in patients undergoing clinically indicated coronary OCT imaging. Patients were randomly assigned to undergo OCT imaging with either IOCM or LOCM as the initial contrast medium. Following a washout period, a second run of OCT imaging of the same coronary vessel was performed using the other contrast medium. A total of 62 patients were randomized to IOCM first (n = 31) or LOCM first (n = 31). Mean patient age was 65.9 ± 11.2 years and 74.2% were male, with high prevalence of dyslipidemia (82.3%) and prior myocardial infarction (41.9%). Percutaneous coronary intervention was performed in 60 cases (96.8%) and the left anterior descending artery was the most common target vessel (53.3%). The contrast volume used for OCT imaging was similar for IOCM and LOCM (8.0 [6.9, 9.0] mL vs 8.0 [6.7, 9.0] mL; P = .89), as was the length of clear OCT images (70.0 [62.8, 74.0] mm for IOCM vs 70.0 [64.0, 74.0] mm for LOCM; P = .65). Electrocardiographic changes were observed in 11 runs with IOCM (ventricular repolarization changes in 9 runs and premature ventricular contractions [PVCs] in 2 runs) vs 12 runs with LOCM (ventricular repolarization changes in 9 runs and PVCs in 3 runs). The use of IOCM in coronary OCT is associated with similar contrast volume and clear imaging length when compared with LOCM.