Deficiency of angiopoietin-like 3 (ANGPTL3), an inhibitor of lipoprotein lipase, is associated with a reduced risk of coronary artery disease (CAD), according to a study that involved atherosclerotic phenotyping of three individuals with complete ANGPTL3 deficiency, a population-based genomic analysis of ANGPTL3 loss-of-function variants, and a biomarker study in patients with myocardial infarction (MI). None of the individuals with complete ANGPTL3 deficiency had coronary atherosclerotic plaques, and heterozygous carriers of a ANGPTL3 loss-of-function mutation (approximately 1 in 309 of people analyzed) had a 34% decreased risk of CAD compared with noncarriers (OR 0.66, 95% CI 0.44–0.98, P = 0.04). Heterozygous carriers also had lower plasma levels of triglycerides and LDL cholesterol. Plasma ANGPTL3 levels were lower in healthy individuals than in patients with MI, and those in the lowest tertile of ANGPTL3 levels had a 35% reduced risk of MI. ANGPTL3 inhibitors are already in clinical development.