Higher levels of angiotensin-converting enzyme 2 (ACE2) in plasma are associated with a greater risk of major cardiovascular disease (CVD) events, according to a global, population-based study. ACE2 is a component of the counter-regulatory renin–angiotensin system, which has important roles in various CVDs. Moreover, ACE2 is the receptor used by SARS-CoV-2, the virus that causes COVID-19, to enter host cells. Therefore, understanding the function and prognostic role of ACE2 is of increasing importance.A study including 10,753 participants from the PURE study, which enrolled participants from 14 countries across five continents, now shows that high ACE2 levels in plasma are associated with an increased risk of all-cause death as well as cardiovascular and non-cardiovascular deaths. Plasma ACE2 levels were also associated with a higher risk of incident heart failure, myocardial infarction, stroke and diabetes mellitus, independently of age, sex, ancestry and traditional risk factors for CVD. Except for incident heart failure, all associations remained significant after adjusting for B-type natriuretic peptide levels. Moreover, plasma ACE2 level was the highest-ranked predictor of death compared with established risk factors for CVD (smoking, diabetes, blood pressure, blood lipids and BMI) and was a better predictor of heart failure, stroke and myocardial infarction than several of the established risk factors. Men had higher plasma ACE2 levels than women; ACE2 levels varied by ancestry; and higher BMI, older age, diabetes, higher blood pressure, higher LDL-cholesterol level and smoking were associated with increased plasma ACE2 levels.