Measurement of any heterogeneous substance poses a challenge. HDL-cholesterol (HDL-C) is no exception. Numerous methods, based on different principles, have been widely adopted and these different methods often give significantly different values for HDL-C. The paper of Okazaki et al. (1), in this issue, demonstrates the inadequacy of a phosphotungstate precipitation method for HDL-C and proposes the use of HPLC as a tool to compare analytical methods for HDL-C. Interest in developing and evaluating methods for the measurement of HDL-C has origins in two separate arenas—one clinical, reflecting increased attention to HDL-C as a risk factor for coronary heart disease (CHD), and the other economic, reflecting increased emphasis on finding more-cost-effective ways to measure HDL-C. Although HDL-C has long been recognized as a factor in the development of CHD, it has not received nearly the attention given to LDL-cholesterol. Much of the primary and secondary prevention effort is based on risk as defined by LDL-cholesterol. Treatment is targeted at reducing LDL-cholesterol, and success of therapies is judged by their impact on LDL-cholesterol. Nevertheless, in many studies, HDL-C has been shown to be a stronger predictor of risk of CHD than LDL-cholesterol. For example, in the Framingham Heart Study, a 1% increase in LDL-cholesterol translated to a 2% increase in risk, whereas a 1% decrease in HDL-C translated into a 3–4% increase in risk (2). In the Helsinki Heart Study, in those subjects with high LDL-cholesterol (Frederickson Type IIa hyperlipidemia), the greatest predictive value for CHD was low HDL-C, not the severity of the LDL-cholesterol increase (3). In a review of nine different prospective studies in women, HDL cholesterol emerged as the single most important lipid risk factor in women (4). Recently, the National Cholesterol Education Panel released the Adult Treatment …