To determine if non-high-density lipoprotein (HDL) cholesterol is a more useful predictor of coronary heart disease (CHD) risk than low-density lipoprotein (LDL) cholesterol and if very-low-density lipoprotein (VLDL) cholesterol is an independent predictor of CHD risk, data from the Framingham Heart Study (2,693 men, 3,101 women) were used for this analysis. All subjects were aged > or =30 years and free of CHD at baseline, and incident CHD was the end point (618 men, 372 women). Cox proportional-hazards models were used to assess the risk for CHD (relative risks and 95% confidence intervals) on the basis of the joint distribution of LDL cholesterol and non-HDL cholesterol (in milligrams per deciliter), as well as LDL cholesterol, non-HDL cholesterol, and VLDL cholesterol as continuous variables. After multivariate adjustment, within non-HDL cholesterol level, no association was found between LDL cholesterol and the risk for CHD, whereas within LDL cholesterol levels, a strong positive and graded association between non-HDL cholesterol and risk for CHD was observed. When the analysis was repeated within triglyceride levels (<200 vs > or =200 mg/dl), the risk pattern did not change significantly. Also, VLDL cholesterol was found to be a significant predictor of CHD risk after adjusting for LDL cholesterol at triglyceride levels of > or =200 or <200 mg/dl. In conclusion, these results suggest that non-HDL cholesterol level is a stronger predictor of CHD risk than LDL cholesterol; that is, VLDL cholesterol may play a critical role in the development of CHD.