The use of non-invasive imaging to identify ruptured or high-risk coronary atherosclerotic plaques would represent a major clinical advance for prevention and treatment of coronary artery disease. We used combined PET and CT to identify ruptured and high-risk atherosclerotic plaques using the radioactive tracers 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG). In this prospective clinical trial, patients with myocardial infarction (n=40) and stable angina (n=40) underwent 18F-NaF and 18F-FDG PET-CT, and invasive coronary angiography. 18F-NaF uptake was compared with histology in carotid endarterectomy specimens from patients with symptomatic carotid disease, and with intravascular ultrasound in patients with stable angina. The primary endpoint was the comparison of 18F-fluoride tissue-to-background ratios of culprit and non-culprit coronary plaques of patients with acute myocardial infarction. In 37 (93%) patients with myocardial infarction, the highest coronary 18F-NaF uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 IQR 1·40–2·25 vs highest non-culprit 1·24 1·06–1·38, p<0·0001). By contrast, coronary 18F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and non-culprit plaques (1·71 1·40–2·13 vs 1·58 1·28–2·01, p=0·34). Marked 18F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. 18 (45%) patients with stable angina had plaques with focal 18F-NaF uptake (maximum tissue-to-background ratio 1·90 IQR 1·61–2·17) that were associated with more high-risk features on intravascular ultrasound than those without uptake: positive remodelling (remodelling index 1·12 1·09–1·19 vs 1·01 0·94–1·06; p=0·0004), microcalcification (73% vs 21%, p=0·002), and necrotic core (25% 21–29 vs 18% 14–22, p=0·001). 18F-NaF PET-CT is the first non-invasive imaging method to identify and localise ruptured and high-risk coronary plaque. Future studies are needed to establish whether this method can improve the management and treatment of patients with coronary artery disease. Chief Scientist Office Scotland and British Heart Foundation.