Background: Coronary endothelial function and atherosclerotic plaque progression have both been shown to be associated with adverse cardiovascular events. However, the relationship between these factors and the lipid burden of coronary plaque remains unknown. Purpose: To investigate the relationship between impaired coronary endothelial function and the natural history of lipid rich plaque (LRP). Methods: 33 patients with stable angina or ACS underwent serial assessment of coronary endothelial function and plaque imaging by dual modality intravascular ultrasound and near infrared spectroscopy. Salbutamol and glyceryl trinitrate (GTN) were used as the endothelium dependent and independent vasoreactive stimulus respectively. Coronary segmental macrovascular response [% change segmental lumen volume (SLV)], plaque burden [per cent atheroma volume (PAV)], and lipid core [LRP and lipid core burden index (LCBI)] were measured at baseline and after an interval of 12–18 months (N=520 consecutive 2-mm coronary segments). Results: Coronary segments which progress into LRP demonstrated greater reduction in vasodilator response to salbutamol (-0.24±2.96 vs 5.60±1.47%, p=0.04) and GTN (13.91±4.45 vs 21.19±3.19%, p=0.036), at baseline. By multivariate analysis, increase in lipid core was independently predicted by reduced baseline coronary endothelium dependent vasodilator function (table), whereas increase in atheroma volume was predicted by baseline coronary endothelial independent function (β coefficient: 0.21, 95% CI (0.09 to 0.33), p=0.0005). In the secondary analysis, serial changes in coronary endothelial independent function was associated with changes in plaque volume (β coefficient: -0.06, 95% CI (-0.09 to -0.02), p=0.001). There is poor correlation between atheroma volume growth and plaque compositional change (β coefficient -0.35, p=0.721). Conclusions: Epicardial coronary endothelial dependent function is a major determinant of LRP progression irrespective of the nature of clinical presentation.