Recent studies have suggested that milk and certain dairy food components have the potential to protect against cardiovascular disease. In order to determine whether the addition of milk-derived phospholipids to the diet results in an improvement in metabolic and cardiovascular risk factors, we studied four groups (n=10) of C57BL/6 mice that were fed: (1) a normal non-purified diet (N); (2) the normal non-purified diet supplemented with phospholipid-rich dairy milk extract (PLRDME, 2.5% by wt) (NPL); (3) a high-fat semi-purified diet (HF) containing 21% butterfat+0.15% cholesterol by wt; or (4) HF supplemented with 2.5% by wt PLRDME (HFPL). Dietary PLRDME supplementation did not have a significant effect on metabolic parameters in mice fed the N diet. In contrast, in high-fat fed mice, PLRDME caused a significant decrease in: (a) liver wt (1.57+/-0.06 g vs. 1.20+/-0.04 g, P<0.001), (b) total liver lipid (255+/-22 mg vs. 127+/-13 mg, P<0.001, (c) liver triglyceride (TG) and total cholesterol (TC) 236+/-25 micromol/g vs. 130+/-8 micromol/g (P<0.01), 40+/-7 micromol/g vs. 21+/-2 micromol/g (P<0.05), respectively); and serum lipids (TG: 1.4+/-0.1 mmol/L vs. 1.1+/-0.1 mmol/L, P=0.01; TC: 4.6+/-0.2 mmol/L vs. 3.6+/-0.2 mmol/L, P<0.001; and PL: 3.3+/-0.1 mmol/L vs. 2.6+/-0.1 mmol/L, P<0.01). These data indicate that dietary PLRDME has a beneficial effect on hepatomegaly, hepatic steatosis and elevated serum lipid levels in mice fed a high-fat diet, providing evidence that PLRDME might be of therapeutic value in human subjects as a hepatoprotective or cardioprotective nutraceutical.