Objectives The purpose of this study was to quantify the effects of coronary atherosclerosis morphology and extent on myocardial flow reserve (MFR). Background Although the relationship between coronary stenosis and myocardial perfusion is well established, little is known about the contribution of other anatomic descriptors of atherosclerosis burden to this relationship. Methods We evaluated the relationship between atherosclerosis plaque burden, morphology, and composition and regional MFR (MFRregional ) in 73 consecutive patients undergoing Rubidium-82 positron emission tomography and coronary computed tomography angiography for the evaluation of known or suspected coronary artery disease. Results Atherosclerosis was seen in 51 of 73 patients and in 107 of 209 assessable coronary arteries. On a per-vessel basis, the percentage diameter stenosis (p = 0.02) or summed stenosis score (p = 0.002), integrating stenoses in series, was the best predictor of MFRregional . Importantly, MFRregional varied widely within each coronary stenosis category, even in vessels with nonobstructive plaques (n = 169), 38% of which had abnormal MFRregional (<2.0). Total plaque length, composition, and remodeling index were not associated with lower MFR. On a per-patient basis, the modified Duke CAD (coronary artery disease) index (p = 0.04) and the number of segments with mixed plaque (p = 0.01) were the best predictors of low MFRglobal. Conclusions Computed tomography angiography descriptors of atherosclerosis had only a modest effect on downstream MFR. On a per-patient basis, the extent and severity of atherosclerosis as assessed by the modified Duke CAD index and the number of coronary segments with mixed plaque were associated with decreased MFR.