Epidemiological evidence suggests that plasma high-density lipoprotein (HDL) is protective against coronary artery disease, whereas oxidatively modified low density lipoprotein is atherogenic. Human apolipoprotein A-I transgenic mice with overexpression of the human apolipoprotein A-I gene have increased plasma levels of apolipoprotein A-I and HDL-cholesterol. We analyzed LDL oxidation by determination of LDL associated malondialdehyde, peroxides and conjugated dienes. The present study demonstrates that HDL from both normal and human apolipoprotein A-I transgenic mice at similar concentrations inhibits LDL (protein concentration 500 mg/l) lipid peroxidation, but the effect of the human apolipoprotein A-I transgenic mice HDL was two-fold greater than that of HDL derived from normal mice. In addition, the electrophoretic mobility of oxidatively modified LDL was reduced about two-fold in the presence of human apolipoprotein A-I transgenic mice HDL than that obtained in the presence of normal mice HDL. We thus suggest that human apolipoprotein A-I possesses antioxidant properties which might neutralize LDL lipid peroxidation. This may underline the mechanism responsible for the lower prevalence of atherosclerosis in subjects with high plasma levels of HDL and apolipoprotein A-I.