Semipurified lithogenic diets for hamsters contain casein as the protein source. Since substitution of soy protein isolate for casein reduces serum cholesterol concentrations in several species, we studied replacement of casein by soy protein for effects on gallstone formation. Feeding soy protein consistently resulted in a significantly reduced incidence of gallstones. Switching to a soy-based diet after induction of gallstones resulted in dissolution of a significant percentage of the stones. Partial substitution of soy for casein gave results intermediate between 100% casein and 100% soy. The lysine/arginine ratio of the proteins may be responsible for the observed differences in cholelithiasis. The reduction in lithogenicity associated with feeding soy protein appears to be mediated primarily through decreased secretion of cholesterol into bile.