Coronary computed tomography angiography (CCTA) plaque morphology based on conventional Hounsfield units relies on absolute CT numbers is influenced by imaging and anatomical variables. The project describes and tests a novel alternative method, termed the "labeling method", which uses relative CT numbers and 3-dimensional plaque structure. Using virtual histology intravascular ultrasound (VH-IVUS) as the reference standard, this study compares the labeling method to a conventional CT-number based method to determine coronary plaque morphology. Thirty-seven high-risk, non-calcified atherosclerotic coronary lesions were prospectively evaluated in 33 consecutive patients who underwent CCTA followed by VH-IVUS (mean interval 8.6 ± 13.3 days). CCTA-derived vessel and minimum lumen areas were compared to VH-IVUS measures. Fibrotic and necrotic core areas were calculated by both the labeling method to the CT-number based method; both were tested for agreement with reference standard VH-IVUS. Inter- and intra-observer correlations were assessed. CCTA significantly underestimated minimum lumen area when compared to VH-IVUS (mean difference -1.4 ± 0.9 mm(2), p < 0.0001). Necrotic core and fibrous areas quantified using the labeling method demonstrated superior correlation with VH-IVUS compared to those quantified using the CT-number based method, Pearson's r = 0.75 versus 0.42 and r = 0.80 and 0.59, respectively. Compared to VH-IVUS, limits of agreement for the labeling method-derived necrotic core (-2.0 to 2.5 mm(2)) and fibrous areas (0.6-8.0 mm(2)) were more narrow than those determined using the CT-number based method (-3.7 to 7.3 and -4.0 to 8.9 mm(2), respectively). Inter- and intraobserver correlations were excellent for all CCTA derived measures (r = 0.85-0.98). A novel CCTA-based labeling method offers an alternative to conventional CT-number based analyses for plaque morphology. The labeling method demonstrates superior correlation to VH-IVUS for measures of fibrotic and necrotic core areas within non-calcified coronary atherosclerotic plaques.