Hyperlipidemia has been demonstrated to be associated with renal disease, yet the mechanism of renal injury is still poorly understood. Inflammation that occurs with the hyperlipidemia has been considered to play an important role in development of glomerular injury. Here, we investigated the role of interleukin-6 (IL-6), a key inflammatory molecule, on renal injury in apolipoprotein E-deficient mice with severe hypercholesterolemia. The 6 week old mice were fed a high-fat diet and administered weekly rat anti-IL-6 receptor monoclonal antibody, MR16-1; control rat IgG; or saline for a total of 4 weeks. We examined histopathological changes in the kidney and urinary excretion of protein and albumin. Saline- and IgG-treated mice showed remarkable proteinuria at 10 weeks of age, while MR16-1-treated mice exhibited significantly lower levels. Renal histopathology of saline- and IgG-treated mice revealed striking lipid deposits and foam cells in the glomerular tuft, juxtaglomerular area, and arteriolar wall along with range of mesangial cell proliferation and matrix expansion. Notably, the severity of lipid deposits and mesangial cell proliferation were significantly reduced in MR16-1treated mice. Immunohistochemistry demonstrated that mesangial IL-6 expression was dramatically reduced in MR16-1 mice compared with IgG mice. Blocking the IL-6 receptor prevented progression of proteinuria and renal lipid deposit, as well as the mesangial cell proliferation associated with severe hyperlipoproteinemia. These results clearly demonstrate that IL-6 plays an essential role in the pathogenesis of hyperlipidemia-induced glomerular injury in ApoE-/- mice and suggests the usefulness of anti-IL-6 receptor antibody in treatments for hyperlipidemia-induced organ damage