Hepatic triglyceride lipase (HL) is thought to play a role in the formation of low density lipoproteins (LDLs) from small very low density lipoproteins (VLDLs) and intermediate density lipoproteins (IDLs). To analyze the possible physiological role of HL in determining LDL buoyancy, size, and chemical composition, HL activity and LDL were studied in 21 patients with coronary artery disease (CAD) and 23 normolipidemic subjects. In both groups, LDL buoyancy and size were inversely associated with HL activity levels. The effect of HL on LDL size was comparable in CAD patients and in normolipidemic subjects. HL appeared to influence LDL lipid composition primarily by affecting the surface lipid components. The free cholesterol content of LDL particles was highly correlated with HL activity in both CAD and normolipidemic individuals. The free cholesterol to phospholipid ratio in LDL particles correlated with HL in both CAD and normolipidemic subjects. When the individuals were separated according to their LDL subclass patterns, pattern B subjects had significantly higher HL than pattern A subjects in both CAD and normolipidemic groups. The analysis of the cholesterol distribution profiles across the lipoprotein density gradient confirmed that LDL buoyancy is affected by HL. These data support the hypothesis that HL modulates the physical and compositional properties of LDL and contributes to the expression of the LDL subclass phenotype. suggesting a physiological role for HL in LDL metabolism.