An E40K loss-of-function variant in the ANGPTL4 gene is associated with substantially reduced plasma triglyceride levels in white persons, but its association with cardiovascular disease occurrence has not been reported. The prospective, population-based Atherosclerosis Risk in Communities Study measured the E40K ANGPTL4 variant in approximately 10000 white participants and determined its association with coronary heart disease (CHD) incidence (n = 1318 events) between 1987-1989 and 2004. Compared with noncarriers, carriers of 1 or 2 copies of the 40K variant (3.8% frequency) had a 19-mg/dL lower age- and sex-adjusted mean triglyceride level, 5-mg/dL lower low-density lipoprotein cholesterol, and 4-mg/dL higher high-density lipoprotein cholesterol. The age-, sex-, and field center-adjusted hazard ratio of CHD was 0.63 (95% confidence interval, 0.45-0.89). Adjustment for nonlipid confounding factors did not change this hazard ratio appreciably. Carriers also appeared to have reduced risk of incident stroke, prevalent peripheral artery disease, and carotid atherosclerosis; but these associations were based on few events among 40K carriers and were not statistically significant. In conclusion, in this prospective study, the 40K variant of ANGPTL4 appeared to confer reduced genetic risk for CHD.