Discordance between angiography-based anatomical assessment of coronary stenosis severity and fractional flow reserve (FFR) has been attributed to several factors including lesion length and irregularity, and the myocardial territory supplied by the target vessel. We sought to examine if coronary arterial distensibility is an independent contributor to this discordance. There were two parts to this study. The first consisted of “in silico” models of 26 human coronary arteries. Computational fluid dynamics-derived FFR was calculated for fully rigid, partially distensible and fully distensible models of the 26 arteries. The second part of the study consisted of 104 patients who underwent coronary angiography and FFR measurement. Distensibility at the lesion site (DistensibilityMLA) and for the reference vessel (DistensibilityRef) was determined by analysing three-dimensional angiography images during end-systole and end-diastole. Computational fluid dynamics-derived FFR was 0.67±0.19, 0.70±0.18 and 0.75±0.17 (P<0.001) in the fully rigid, partially distensible and fully distensible models respectively. FFR correlated with both DistensibilityMLA (r = 0.36, P<0.001) and DistensibilityRef (r = 0.44, P<0.001). Two-way ANCOVA analysis revealed that DistensibilityMLA (F (1, 100) = 4.17, p = 0.031) and percentage diameter stenosis (F (1, 100) = 60.30, p < 0.01) were both independent predictors of FFR. Coronary arterial distensibility is a novel, independent determinant of FFR, and an important factor contributing to the discordance between anatomical and functional assessment of stenosis severity.