Scavenger receptor BI (SR-BI) is known to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE) in liver and steroidogenic tissues. To evaluate the role of SR-BI in plasma lipoprotein metabolism, we have generated transgenic mice with liver-specific overexpression of murine SR-BI. On a chow diet SR-BI transgenic (SR-BI Tg) mice have decreased HDL-CE, apoA-I, and apoA-II levels; plasma triglycerides, low density lipoprotein (LDL) cholesterol, and very low density lipoprotein (VLDL) and LDL apoB were also decreased, compared with control mice. Turnover studies using non-degradable CE and protein labels showed markedly increased total and selective uptake of HDL-CE in the liver and increased HDL protein catabolism in both liver and kidney. To evaluate the changes in apoB further, mice were challenged with high fat, high cholesterol diets. In SR-BI Tg mice plasma apoB levels were only 3-15% of control levels, and the dietary increase in VLDL and LDL apoB was virtually abolished. These studies show that steady state overexpression of hepatic SR-BI reduces HDL levels and increases reverse cholesterol transport. They also indicate that SR-BI can play a role in the metabolism of apoB-containing lipoproteins. The dual effects of increased reverse cholesterol transport and lowering of apoB-containing lipoproteins that result from hepatic SR-BI overexpression could have anti-atherogenic consequences.