Dyslipidemia is a prominent feature of chronic renal failure (CRF) and a major risk factor for atherosclerosis and progression of renal disease. CRF-induced dyslipidemia is marked by hypertriglyceridemia and a shift in plasma cholesterol from HDL to the ApoB-containing lipoproteins. Several studies have demonstrated favorable response to administration of HMGCoA reductase inhibitors (statins) in CRF. This study was intended to explore the effect of statin therapy on key enzymes and receptors involved in cholesterol metabolism. Accordingly, CRF (5/6 nephrectomized) and sham-operated rats were randomized to untreated and statin-treated (rosuvastatin 20 mg/kg/day) groups and observed for 6 weeks. The untreated CRF rats exhibited increased total cholesterol-to-HDL cholesterol ratio, diminished plasma LCAT and hepatic LDL receptor, elevated hepatic ACAT and no change in hepatic HMG-CoA reductase, cholesterol 7-hydroxylase or HDL receptor (SRB-1). Statin administration lowered HMG-CoA reductase activity, normalized plasma LCAT, total cholesterol to HDL cholesterol ratio and hepatic LDL receptor, but did not significantly change either plasma total cholesterol, hepatic cholesterol 7- hydroxylase, total ACAT activity or SRB-1 in the CRF animals. Statin administration to the normal control rats led to significant increases in plasma LCAT and hepatic LDL receptor, significant reductions of total cholesterol to HDL cholesterol ratio, hepatic HMG-CoA reductase activity and cholesterol 7-hydroxylase abundance with virtually no change in plasma cholesterol concentration. Thus, administration of rosuvastatin reversed LCAT and LDL receptor deficiencies and promoted a shift in plasma cholesterol from ApoB-containing lipoproteins to HDL in CRF rats.