We analyzed data from a population-based survey to determine whether serum high-density lipoprotein cholesterol (HDL-C) concentrations are different in blacks and whites after controlling for life-style characteristics. We studied a total of 741 white men, 453 black men, 786 white women, and 572 black women age 35-74 years. Age-adjusted HDL-C concentrations were higher in black than white men (48.6 vs 40.8 mg/dl) and in black than white women (56.1 vs 54.0 mg/dl). Life-style characteristics associated with HDL-C in women were exogenous hormone use, average number of cigarettes smoked per day, average ounces of alcohol consumed per week, body mass index, and use of beta-blockers. Life-style characteristics associated with HDL-C levels in men included age, average number of cigarettes smoked per day, average ounces of alcohol consumed per week, body mass index, and a self-reported history of diabetes. After adjustment for life-style characteristics, black men and women had HDL-C levels 7.0 and 5.3 mg/dl higher, respectively, than whites. Body mass index was a negative confounder in women; after adjusting for body mass and age, black women had HDL-C levels 4.6 mg/dl higher than white women. These data indicate that the measured life-style factors cannot fully explain the observed differences in HDL-C between blacks and whites. These findings, which are consistent with other reports, may reflect an inability to assess life-style factors accurately and/or genetic or cultural factors yet to be determined.