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High-density lipoprotein cholesterol (HDL-C) has been identified as an independent inverse predictor of coronary heart disease, leading to the inclusion of HDL-C in certain risk engines. However, negative results also exist and create confusion regarding the value of interventions that increase HDL-C. The possible reasons for these conflicting findings are many, including not only patient selection (e.g. baseline HDL-C levels) but also the effect of the treatment on the quantity and quality of HDL. In the present review, the results of some HDL-C trials are discussed. They suggest that HDL-C function as well as quantity is clinically relevant. Furthermore, ‘dysfunctional’ HDL may be present in conditions such as diabetes or acute coronary syndromes. Efforts should focus on improving HDL particle functionality in addition to a numerical increase in HDL-C levels.