In 12 years of follow-up for 2748 Framingham Heart Study participants ages 50 to 79, low levels of high density lipoprotein cholesterol (HDL-C) were associated with increased mortality. For men, the relative risk of death in the first HDL-C quintile (less than 35 mg/dl) as compared to the top quintile (greater than 54 mg/dl) was 1.9 for all causes, and 3.6 and 4.1 for death due to cardiovascular and coronary heart disease (CHD), respectively, after adjustment for standard cardiovascular risk factors. In women, corresponding relative risks, comparing the bottom HDL-C quintile (less than 45 mg/dl) to the top quintile (greater than 69 mg/dl), were 1.5, 1.6, and 3.1. With HDL-C considered as a continuous variable, and after adjustment for standard cardiovascular risk factors, highly significant associations were seen with HDL-C and CHD death in both men and women. In addition, a significant HDL-C effect on total mortality and death due to cardiovascular disease was seen in men. In none of the continuous variable analyses was HDL-C associated with cancer death. We conclude that HDL-C is a potent predictor of CHD death in both sexes and has less consistent associations with other types of death.