Coronary endothelial-dependent microvascular dysfunction, an early reversible stage of coronary artery disease (CAD), is associated with poor clinical outcome. The current study investigated whether coronary artery distensibility index (CDI) is associated with: (i) coronary endothelial-dependent microvascular dysfunction and (ii) vulnerable plaque composition among subjects with non-obstructive CAD. Seventy-four subjects with non-obstructive CAD (luminal stenosis <30%) were studied. In 20 subjects with and without coronary endothelial-dependent microvascular dysfunction, coronary flow reserve (CFR) of target segment during intracoronary (IC) infusion of acetylcholine (Ach) and bolus injection of adenosine as well as CDI at rest of corresponding target segment were measured. In 54 subjects, plaque compositions and CDI at rest of 154 non-obstructive coronary segments as well as proximal segment without disease were measured by intravascular ultrasound (IVUS). CDI was defined as: [(Early-diastolic cross-sectional-area (CSA) – End-diastolic CSA of target segment)/(end-diastolic CSA of target segment × coronary-pulse-pressure) × 103]. There is a direct association between endothelial dysfunction and impaired CDI of a coronary segment both in the given coronary segment and corresponding microvessels in which a strong agreement between CDI and CFR Ach (r2 = 0·85, P = 0·0001) was observed. Multivariable regression-analysis showed that CDI was an independent predictor of the vulnerable plaque characteristics. The risk of impaired CDI was 125% higher in segments with necrotic core and 60% higher in segments with fibrofatty components as compared to normal segments (P = 0·001). In conclusions, the current study reveals that impaired CDI is an endothelial-dependent process of both given coronary segment and corresponding microvessels and is associated with vulnerable plaque composition.