Little is known about individuals who have very high values of serum high-density lipoprotein cholesterol (HDL-C) with the exception of those who have very rare genetic conditions, eg, familial hyperalphalipoproteinemia or hypobetalipoproteinemia. During a period of 60 months of testing for HDL-C, we found 46 individuals (of whom 43 were women) who had an HDL-C level equal to or higher than 2.58 mmol/L (greater than or equal to 100 mg/dL) (range, 2.58 to 6.15 mmol/L [100 to 238 mg/dL]). Sixteen of these individuals were treated with estrogens or ranitidine or were alcoholic, and several had evidence of coronary heart disease. We conclude that very high values of HDL-C can be found in the general population mostly in women, and this is often related to environmental causes, eg, the use of H2-blockers, estrogens, and alcohol. The finding of very elevated HDL-C levels in serum is probably not always due to a genetic condition and does not always signify absence of coronary heart disease and increased life expectancy.