Epidemiological studies have enhanced the importance of high-density lipoprotein (HDL) as a risk factor for CAD, as well as disability and frailty in the oldest elderly. Therefore, HDL and molecules involved in HDL metabolism seem to be attractive candidates for longevity-promoting factors. A series of observational studies has demonstrated that the predominance of the larger, more lipid-rich HDL2 subclass is a reproducible phenotype among centenarians. This finding was recently evolved by nuclear magnetic resonance technology in quantification of lipoprotein particle size. However, results of investigations into the mechanisms underlying the lipoprotein profiles in the oldest elderly have been conflicting. Genetic variation in cholesteryl ester transfer protein (CETP), which is a carrier protein in reverse cholesterol transport, was demonstrated to have no association with longevity in one study, but to have positive impacts on large HDL particles and longevity in another. Regarding environmental factors, acute phase reactant and nutritional status are frequently associated with HDL-C levels in the oldest elderly, however, the causality of the association remains to be elucidated. Determination of the association between cognitive function and HDL in the oldest elderly is also a future task. To obtain further insight into the mechanistic roles of low HDL in the pathophysiology of geriatric syndrome, a much greater effort should be invested in this research field.