Aim To investigate the effects of probucol on high fat-high cholesterol(HFHC)diet-induced hyperlipidemia and oxidative stress in apo E deficient(apoE-/-)mice and genetic background C57BL/6J mice.Methods The hyperlipidemic mice were induced by feeding HFHC diet which was supplemented with 15%lard and 0.25% cholesterol.The levels of plasma lipids were determined by standard assays.The oxidative stress was evaluated by the serum levels of total antioxidant capacity(T-AOC),superoxide dismutase(SOD),and malonic dialdehyde(MDA)determined by commercially provided kits.The aortic atherosclerotic lesions were demonstrated by Sudan IV staining.Activity of paraoxonase 1(PON1)was assessed by modified Echerson's method.Expression level of PON1 in liver was evaluated by semi-quantitative reverse-transcription-polymerase reaction(RT-PCR).Results HFHC diet elevated the levels of serum triglyceride(TG),total cholesterol(TC),low density lipoprotein-cholesterol(LDLC),and high density lipoprotein-cholesterol(HDLC).Probucol decreased the elevation of serum levels of lipids.In C57BL/6J mice,the levels of TG,TC,LDLC,and HDL-C lowered 41%,43%,44.8%,and 41.3%,respectively,compared with control group(P<0.05).In apo E-/-mice,decrease of 36.2%,28.2%,31.3%,and 33.9%,respectively,was observed versus apo E-/-control(P<0.05).Probucol treatment prevented the atherosclerotic lesion development in both C57BL/6J and apoE-/-mice.Compared with HFHC groups,the aorta lesions were significantly decreased by 61.1% in C57BL/6J mice and by 27.2% in apo E-/-mice(P<0.05),respectively,after treatment of probucol.Admi-nistration of probucol lowered the serum levels of MDA and oxLDL,and elevated the levels of serum T-AOC and SOD.The results also demonstrated a more significant increase of PON1 activity and expression level in C57BL/6J mice than in apo E-/-mice.Conclusion Probucol decreases the levels of serum lipids and alleviates the atherosclerotic lesions in HFHC diet-induced hyperlipidemic mice.Probucol may contribute to a significant decrease of the oxidative stress.The effects of probucol may be attenuated by apo E deficiency in mice.