The objective of this study was to compare the effects of dietary soy protein isolate and casein on atherosclerotic lesion development in apolipoprotein (apo) E–deficient mice. Male C57BL/6J apoE-deficient mice (9–10 wk old) in groups of 6–9 were used in a series of feeding studies. In the first experiment, mice were fed purified diets containing cholesterol (1 g/100 g) and cholate (0.25 g/100 g) for 6 wk; soy protein isolate or casein was used as the protein source. Although serum total cholesterol concentration did not differ between groups, the lesion area of the thoracic aorta in the soy protein isolate group was lower than that of the casein group (P < 0.01). In the second and third experiments, mice were fed the same purified diet as in Experiment 1, only without supplementation of cholesterol and cholate for 24 and 9 wk, respectively. In each of these two experiments, serum total cholesterol concentrations again did not differ between soy protein isolate– and casein-fed groups. Serum homocysteine concentrations did not differ between groups in Experiment 3. Dietary soy protein isolate, compared with casein, lowered the thoracic aorta lesion area (Experiment 2; P < 0.001) and the percentage of the aortic arch inner surface covered by lesions (P < 0.05). In the final experiment, mice were fed the cholesterol-free diets containing ethanol-extracted soy protein isolate or casein plus the soy protein ethanol extracts for 9 wk. There were no differences in serum total cholesterol concentration or thoracic aorta lesion areas between the two groups. These results indicate that the antiatherogenic effect of native soy protein isolate cannot be explained by its effect on serum lipids or homocysteine and suggest that both the protein component and the ethanol extracts of the soy protein isolate may contribute to the antiatherogenic effect of the native soy protein isolate.