We report here a proteomic analysis of differentially expressed liver proteins of both C57BL/6J (B6, atherosclerosis-susceptible strain) and C3H/HeJ mice (C3H, atherosclerosis-resistant strain), which were fed either control or a high-fat enriched atherogenic diet for eight weeks. We observed differential patterns of plasma lipids between the two strains when both were fed atherogenic diets. That is, although low density lipoprotein cholesterol level was highly elevated in both, the levels of total cholesterol and triglyceride in B6 mice were much lower than those in C3H mice when they were fed atherogenic diets. However, the high density lipoprotein cholesterol level was increased in the latter but decreased in the former. Histopathological observation revealed that more prominent lipid droplets were present in B6 mice than in C3H mice, when they were maintained on the atherogenic diets. Proteomic analysis of liver tissues of these two strains showed that a total of 30 proteins were significantly changed in the livers obtained from both strains after being fed the atherogenic diet. Of these, 14 protein spots including carbonic anhydrase III, senescence marker protein 30 and selenium binding protein 2 were differentially changed only in B6 mice, which was also confirmed in part by Western blotting. An additional 16 protein spots including glutathione S-transferase subclass, apolipoprotein E and chaperonin proteins were changed in both strains. We also identified 28 proteins that were differentially expressed in the livers of both B6 and C3H mice, regardless of diet feeding condition. Of these, 4 protein spots in B6 mice and 11 protein spots in C3H mice were up-regulated. Thirteen strain specific protein spots including antioxidant protein 2, apolipoprotein E and apolipoprotein A-I were also detected in different positions in two-dimensional electrophoresis. These results suggest a clear distinction in differential expression of oxidative stress proteins and lipid metabolism related proteins between the two strains in response to atherogenic diet feeding, which might account for their difference in susceptibility to atherogenesis.