OBJECTIVES: This study investigated the role of fractional myocardial mass (FMM), a vessel-specific myocardial mass, in the evaluation of physiological severity of stenosis. Using computed tomography angiography, the study investigated fractional myocardial mass, a concept of myocardial mass subtended by specific vessel, which could reduce anatomical-physiological mismatch. BACKGROUND: Discordance between anatomical stenosis and physiological severity is common but remains poorly understood. METHODS: This multicenter study enrolled 463 patients with 724 lesions, who underwent coronary computed tomography angiography (CCTA) and invasive coronary angiography with fractional flow reserve (FFR) measurement. FMM was assessed by allometric scaling analysis of arterial tree length and myocardial mass from CCTA. RESULTS: FFR <0.80, a criteria for vessel-specific physiological stenosis, was found in 281 vessels (39%). FMM decreased consistently according to the vessel downstream (p < 0.001, all). The frequency of FFR <0.80 increased in proportion to FMM and inverse proportion to angiographic minimal luminal diameter (MLD) (p < 0.001). In per-vessel analysis, FMM per MLD (FMM/MLD) showed good correlation with FFR (r = 0.61) and was superior to diameter stenosis (DS) for FFR <0.80 by receiver operating characteristic and reclassification analysis (C-statistics = 0.84 versus 0.74, net reclassification improvement [NRI] = 0.63, integrated discrimination improvement [IDI] = 0.18: p < 0.001, all). The optimal cutoff of FMM/MLD was 29 g/mm, with sensitivity = 75%, specificity = 77%, positive predictive value = 68%, negative predictive value = 83%, and accuracy = 77%. Addition of FMM/MLD to DS could further discriminate vessels with FFR <0.80 (C-statistic = 0.86 vs. 0.84, NRI = 0.34, IDI = 0.03: p < 0.005, all). In per-range classification analysis, agreement between FFR and FMM/MLD maintained >80% when the severity of disease was away from cutoff. CONCLUSIONS: FMM/MLD could find physiological severity of coronary artery with higher accuracy than anatomical stenosis. FMM may explain the anatomical-physiological discordance.