Lipoprotein abnormalities are present in a high proportion of renal transplant patients. It is accepted that dyslipidaemia is associated with atherosclerosis and in the progression of renal disease. Lipid abnormalities may also play a significant role in the development of chronic allograft nephropathy (CAN). Sirolimus was found to have an anti-atherosclerotic effect in the Apo E-knockout mice model of hyperlipidaemia through its anti-proliferative effects. As lipid-mediated renal injury is important in the pathogenesis of glomerulosclerosis which shares common pathogenic mechanisms with atherosclerosis, in this study we have tested the hypothesis that sirolimus prevents lipid-mediated renal injury through the modulation of cholesterol homeostasis of mesangial cells and its anti-inflammatory effects on macrophages. We demonstrated that sirolimus reduced lipid accumulation, as measured by Oil Red O staining in human mesangial cells (HMCs). Using real-time PCR, we screened the mRNA expression of lipoprotein receptors. Sirolimus significantly suppressed LDL and VLDL receptors and CD36 gene expression. It also increased cholesterol efflux from HMCs by increasing PPAR, PPAR, LXR and ABCA1 gene expression. Sirolimus overrode the suppression of cholesterol efflux and ABCA1 gene expression induced by inflammatory cytokine IL-1. Furthermore, sirolimus significantly inhibited inflammatory cytokines IL-6 and TNF production in macrophages. This data suggest that sirolimus may prevent cellular cholesterol accumulation even in the presence of hyperlipidaemia and inflammation, by regulating both cholesterol homeostasis and inflammatory responses.