Hyperlipidemia has been implicated in the pathogenesis of experimental progressive glomerulosclerosis, but its role in human renal injury is controversial. This report describes a 12-yr-old boy presenting with massive proteinuria, hepatomegaly, anemia, severe mixed hyperlipidemia, and progressive renal failure. The initial renal biopsy disclosed large numbers of foam cells that were shown to be monocytes. Evidence is presented suggesting that apoprotein-E2 homozygosity in our patient, together with an 88% reduction in plasma lipoprotein lipase activity associated with severe nephrotic syndrome, is responsible for the atypical clinical features, lipoprotein phenotype III with chylomicronemia, and renal lipidosis. A regimen of dietary lipid restriction, gemfibrozil, and niacin resulted in significant but partial improvement of the dyslipidemia and resolution of the hepatomegaly and ascites. This report stresses the importance of characterizing unique lipid disorders in patients with nephrotic syndrome in order to prescribe effective lipid-lowering strategies. Moreover, the striking resemblance of the clinical and nephrohistologic features of this patient to those occurring in experimental models of coexisting glomerular injury and hyperlipidemia led to the speculation that, in this setting, the hyperlipidemia may contribute to the development of progressive glomerulosclerosis.