Background: We hypothesize that in patients with suspected coronary artery disease (CAD), lower values of the ratio of total epicardial coronary arterial lumen volume to left ventricular myocardial mass (V/M) result in lower fractional flow reserve (FFR). Methods: V/M was computed in 238 patients from the NXT trial who underwent coronary computed tomography angiography (CTA), quantitative coronary angiography (QCA) and FFR measurement in 438 vessels. Nitroglycerin was administered prior to CT, QCA and FFR acquisition. The V/M ratio was quantified on a patient-level from CT image data by segmenting the epicardial coronary arterial lumen volume (V) and the left ventricular myocardial mass (M). Calcified and noncalcified plaque volumes were quantified using semi-automated software. Results: The median value of V/M (18.57 mm(3)/g) was used to define equal groups of low and high V/M patients. Patients with low V/M had greater diameter stenosis by QCA, more plaque and lower FFR (0.80 +/- 0.12 vs. 0.87 +/- 0.08; P < 0.0001) than those with high V/M. A total of 365 vessels in 202 patients had QCA stenosis <= 50% and measured FFR. In these patients, those with low V/M had higher percent diameter stenosis by QCA, greater total plaque volume and lower FFR (0.81 +/- 0.12 vs. 0.88 +/- 0.07; P < 0.0001) than those with high V/M. In multivariate logistic regression analysis, V/M was an independent predictor of FFR <= 0.80 (all p-values < 0.001). Conclusions: Patients with a low V/M ratio have lower FFR overall and in non-obstructive CAD, independent of plaque measures. (C) 2017 The Authors. Published by Elsevier Inc. on behalf of Society of Cardiovascular Computed Tomography.