Hyperlipidemia is a consistent feature of the nephrotic syndrome. In this study, low-density lipoprotein (LDL) metabolism has been investigated in nine patients with nephrotic syndrome and varying degrees of proteinuria. In subjects with moderate proteinuria (less than 10 g/d), total plasma cholesterol values were elevated to approximately 160% of normal due mainly to an increase in circulating LDL cholesterol. Metabolic studies showed that a defect in LDL clearance via the receptor pathway was responsible for its accumulation. The total amount of LDL apolipoprotein catabolized by this mechanism was only 55% of the value seen in controls; 60% more LDL was channelled into alternative, receptor-independent, catabolic pathways. Heavier proteinuria was associated with substantial increases in plasma triglyceride and very-low-density lipoprotein (VLDL) levels. The defect in LDL catabolism was aggravated by oversynthesis of the lipoprotein, which expanded the plasma LDL pool to 250% of normal. These observations indicate that the hyperlipidemia of the nephrotic syndrome is multifactorial in origin. The altered catabolism of LDL may be important in predisposing these subjects to premature atherosclerosis.