Tubular lipidosis is a commonly observed histological lesion in proteinuric renal diseases. We have studied the interaction between native and modified human lipoproteins and human renal proximal tubular cells to investigate whether lipoproteins could be injurious to tubular cells in culture. Human renal proximal tubular cells were cultured and characterized by established methods. Preliminary studies showed that these cells could take up and degrade normal human lipoproteins by high affinity (HDL) and low affinity (LDL) pathways. In subconfluent culture, native lipoproteins, that is, LDL, HDL2 and HDL3, had markedly different effects on cell growth as measured by 3H-thymidine uptake and total cell protein as compared to modified lipoproteins such as minimally modified and oxidized LDL. In addition, we found that renal tubular cells could oxidized native LDL in the presence of copper largely by a superoxide-mediated mechanism. Finally, cellular accumulation of lipid was demonstrated in vitro by incubating cultured cells with varying lipoprotein concentrations for up to 48 hours. Notably, cell detachment was observed only with high concentrations of modified LDL especially with minimally modified LDL. We speculate that uptake and oxidation of filtered LDL by tubular cells may lead to tubular injury in nephrotic states.