Angiographic evaluation of intermediate left main coronary artery stenosis (LMS) is often limited. Three-dimensional (3D) quantitative coronary angiography has recently developed to overcome 2-dimensional (2D) quantitative coronary angiographic (QCA) limitations. In patients with angiographically intermediate LMS, we investigated whether 3D quantitative coronary angiography was superior to 2D quantitative coronary angiography in predicting the presence of a significant LMS, defined as a minimum luminal area <6 mm² at intravascular ultrasound (IVUS). 2D and 3D quantitative coronary angiography were compared in their measurements of minimum luminal area, percent area stenosis, minimum luminal diameter, and percent diameter stenosis and in their prediction of an IVUS minimum luminal area <6 mm². In total 58 target lesions were interrogated, 25 (43%) of which had an IVUS minimum luminal area <6 mm². Correlation between 3D-QCA minimum luminal area and IVUS minimum luminal area was stronger than the correlation between 2D-QCA minimum luminal area (or minimum luminal diameter) and IVUS minimum luminal area (R = 0.67, p = 0.0001, and R = 0.40, p = 0.001, respectively, p = 0.04 for comparison). To predict IVUS minimum luminal area <6 mm², the most accurate 2D-QCA measurement was minimum luminal diameter (area under curve 0.81, cutoff 2.2 mm, p = 0.0001), and the most accurate 3D-QCA measurement was minimum luminal area (area under curve 0.86, cutoff 5.6 mm², p = 0.0001). 2D-QCA percent diameter stenosis did not significantly predict IVUS minimum luminal area <6 mm² (area under curve 0.56, cutoff 38%, p = 0.45). In conclusion, the accuracy of quantitative coronary angiography in predicting LM IVUS minimum luminal area <6 mm² is limited. When IVUS is not available or contraindicated, 3D quantitative coronary angiography may assist in the evaluation of intermediate LMS. Among 2D-QCA parameters, minimum luminal diameter is more accurate than percent diameter stenosis in predicting significant LMS.