We studied the effects of very low density lipoprotein (VDL) obtained from hypertriglyceridemic subjects on the secretion of lipoprotein lipase and lipid accumulation in human monocyte-derived macrophages. The incubation of macrophages with VLDL obtained from different subjects caused different effects on the secretion of lipoprotein lipase (6.8 to 137.7 nM free fatty acid/min/mg cell protein) and triglyceride accumulation (184 to 507 micrograms/mg cell protein) in human monocyte-derived macrophages. VLDL from subjects with marked hypertriglyceridemia (approximately 1000 mg/dl) had a fourfold greater effect on lipoprotein lipase activity and a twofold greater effect on cellular triglyceride accumulation when compared with the effects of VLDL from normolipidemic subjects. Both lipoprotein lipase activity and triglyceride accumulation correlated positively with plasma VLDL triglyceride levels (r = 0.50 and 0.45, respectively, p less than 0.05). From these data, we suggest that the activity of lipoprotein lipase secreted from macrophages incubated with VLDL was dependent on triglyceride concentrations, and that the secretion of lipoprotein lipase enhanced by hypertriglyceridemic VLDL was closely related to the intracellular accumulation of triglyceride.