Low-density lipoprotein (LDL) with apolipoprotein C-III (apoC-III) is the lipoprotein species that most strongly predicts initial and recurring coronary heart disease (CHD) events in several cohorts. Thus, a large portion of the CHD risk conferred by LDL may be attributable to LDL that contains apoC-III. Very-low-density lipoprotein (VLDL) and LDL with apoC-III have varying amounts of apoE. We hypothesized that a high content of apoE lessens the adverse influence of apoC-III on the risk of CHD because it promotes the clearance of VLDL and LDL from plasma.We studied 2 independent cohorts, the Nurses' Health Study, composed of women, and the Health Professionals Follow-up Study, composed of men. These cohorts contributed to this study 322 women and 418 men initially free of CVD who developed a fatal or nonfatal myocardial infarction during 10 to 14 years of follow-up and matched controls who remained free of CHD. The apoE content of LDL with apoC-III was inversely associated with CHD after multivariable adjustment (relative risk for top versus bottom quintile 0.53, 95% CI 0.35 to 0.80). The apoE content of VLDL with apoC-III had a similar inverse association with CHD. The highest risks were associated with a high apoB concentration and a low apoE content of LDL with apoC-III or of VLDL+LDL with apoC-III. The observed associations were in both male and female cohorts and independent of traditional CHD risk factors and of C-reactive protein.An increased apoE content in VLDL and LDL with apoC-III was associated with a lower risk of CHD. Strategies to enrich VLDL and LDL in apoE are worth exploring for the prevention of CHD.