An impressive number of studies published during the past years have demonstrated that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased cardiovascular risk. Nevertheless, more recent data in both ischemic heart disease patients and general population revealed that also considerably increased HDL-C concentration could be associated with enhanced risk of all-cause and cardiovascular mortality, displaying an U-shaped association with adverse outcomes. These paradoxical findings prompted us to review the available information on this matter, concluding that the association between extremely elevated HDL-C and mortality may not be totally unexpected or unpredictable. Some unfavorable consequences of high HDL-C levels are confirmed by epidemiologic data in over-trained subjects, in whom a similar U-shaped curve is also observed between strenuous training and mortality. This review is hence aimed to summarize these evidences, proffering some possible mechanisms underlying this enigmatic association. If this association could be confirmed in further studies, it may be advisable that laboratory reporting of HDL-C should encompass a range of “desirable values” rather than indicating a single lower decision threshold, as has been suggested until presently
