The effects of soy and casein protein on cholesterol metabolism were determined under normocholesterolemic and hypercholesterolemic conditions in male Wistar rats and in Swiss White mice. Hypercholesterolemia was induced by feeding cholesterol and cholic acid in the diet for a period of 2 weeks. Our results demonstrate that there are significant species differences. The hypercholesterolemic effect of exogenous cholesterol was more pronounced in the mouse than in the rat. The rats fed the basal (no cholesterol, no cholic acid) semisynthetic diet containing either soy or casein had plasma cholesterol concentrations similar to those observed in chow-fed controls. However, plasma cholesterol concentrations in the mice fed the basal semisynthetic diet containing either of the two proteins were significantly elevated compared to the control mice fed commercial chow. Rat data demonstrate that the hypercholesterolemia induced by exogenous cholesterol administration is of a lesser magnitude in the presence of soy compared to casein as a dietary protein source. The mice data show that the concentrations of hepatic and biliary cholesterol and plasma triglycerides and in response to exogenous cholesterol are significantly lower in the soy protein diet compared to the casein protein diet.