To study the role of the two postheparin plasma lipolytic enzymes, lipoprotein lipase (LPL) and hepatic lipase (HL) in high density lipoprotein (HDL) metabolism at a population level, we determined serum lipoproteins, apoproteins A-I, A-II, B, and E, and postheparin plasma LPL and HL activities in 65 subjects with a mean HDL-cholesterol of 34 mg/dl and in 62 subjects with a mean HDL-cholesterol of 87 mg/dl. These two groups represented the highest and lowest 1.4 percentile of a random sample consisting 4,970 subjects. The variation in HDL level was due to a 4.1-fold difference in the HDL2 cholesterol (P less than 0.001) whereas the HDL3 cholesterol level was increased only by 32% (P less than 0.001) in the group with high HDL-cholesterol. Serum apoA-levels were 128 +/- 2.2 mg/dl and 210 +/- 2.8 mg/dl (mean +/- SEM) in hypo- and hyper-HDL cholesterolemia, respectively. Serum apoA-II concentration was elevated by 28% (P less than 0.001) in hyperalphalipoproteinemia. The apoA-I/A-II ratio was elevated only in women with high HDL-cholesterol but not in men, suggesting that elevation of apoA-I is involved in hyperalphalipoproteinemia in females, whereas both apoA proteins are elevated in men with high HDL cholesterol. Serum concentration of apoE and its phenotype distribution were similar in the two groups. The HL activity was reduced in the high HDL-cholesterol group (21.2 +/- 1.5 vs. 38.5 +/- 1.8 mumol/h/ml, P less than 0.001), whereas the LPL activity was elevated in the group with high HDL-cholesterol compared to subjects with low HDL-cholesterol (27.8 +/- 1.3 vs. 19.9 +/- 0.8 mumol/h/ml, P less than 0.001). The HL and LPL activities correlated in opposing ways with the HDL2 cholesterol (r = 0.57, P less than 0.001 and r = 0.51, P less than 0.001, respectively), and this appeared to be independent of the relative ponderosity by multiple correlation analysis. The results demonstrate major influence of both HL and LPL on serum HDL cholesterol concentration at a population level.