We sought to explore differences in distribution and morphology of coronary lesions comparing cardiac allograft vasculopathy and native coronary atherosclerosis (NCA) using intravascular imaging with optical coherence tomography (OCT). At the time of routine surveillance angiography, 17 heart transplant (HT) recipients with a history of high-grade cellular rejection (HGR) and 43 HT recipients with none/mild (low)-grade rejection underwent OCT imaging of the left anterior descending and were compared to 60 patients with NCA without HT. Compared with patients with NCA, patients with HGR had similar intima areas but smaller external elastic lamina areas (7.9 mm² [6.3, 11.2] versus 6.6 mm² [4.8, 7.5], p = 0.02) resulting in smaller lumen areas (4.5 mm² [3.4, 6.6] versus 3.3 mm² [2.8, 4.7], p = 0.04) in distal segments and smaller lumen diameters in side branches (1.28 mm [1.19, 1.37] versus 1.09 mm [0.94, 1.24], p = 0.04). Compared with patients with NCA, lesions in patients with HT were more homogeneous, involving the entire coronary vascular tree. Patients with HGR had a higher prevalence of macrophages involving ≥1 quadrant in all 3 segments compared with patients with NCA. The number of microvessels was greater in patients with both HGR and LGR HT versus NCA. In conclusion, distinct findings in the distribution and morphology of coronary lesions between HT recipients and patients with NCA are evident by OCT imaging, suggesting that OCT might be useful to help differentiate cardiac allograft vasculopathy from NCA in vivo.