Animal proteins such as casein are more hypercholesterolemic than soy protein or other plant proteins when fed to rabbits in low-fat, cholesterol-free, semipurified diets. A casein-amino acid mixture produces a hypercholesterolemia similar to that of casein. This appears to be mainly due to lysine and methionine, although other essential amino acids probably contribute to the effect. Arginine appeared to counteract the hypercholesterolemic effects of other essential amino acids. Soy protein gave a lower level of serum cholesterol in rabbits than did a soy protein-amino acid mixture, suggesting the presence of factors in soy protein that counteract the effects of hypercholesterolemic amino acids. Soy protein is also less hypercholesterolemic than casein in other animal species, particularly when the diet contains cholesterol, and substitution of soy protein for animal protein in the diet reduces the concentration of serum cholesterol in humans. This effect is somewhat variable but is generally greater in hypercholesterolemic than in normocholesterolemic subjects. The differing effects of dietary proteins on serum cholesterol concentrations in humans and in rabbits are primarily due to changes in LDL cholesterol, and the hypercholesterolemia produced by dietary casein is associated with down-regulation of hepatic LDL receptors.