A wealth of evidence supports the mechanistic role of high-density lipoprotein cholesterol (HDL-C) in promoting reverse cholesterol transport. HDL-C, therefore, has been postulated to have antiatherogenic properties and termed good cholesterol. Numerous studies have demonstrated higher coronary heart disease (CHD) risk among those with low HDL-C levels, with very high HDL-C levels often viewed as being protective. Yet, pharmacotherapies that increase HDL-C (eg, niacin, cholesterol ester transfer protein inhibitors) have failed to demonstrate reduction in event risk or have even demonstrated a signal toward harm. However, less attention has been paid to those with very high levels of HDL-C, and emerging data from healthy populations suggest that a paradoxical association may be present with higher mortality in this group.1