We examined whether a soy protein isolate or one of its major components (genistein) influences the initiation stage of carcinogenesis via DNA binding studies of 7,12-dimethylbenz[a]anthracene (DMBA) in liver and mammary tissue of female CD rats. A semipurified high-fat diet (23.5% corn oil) containing the soy protein isolate (10%), genistein (111 ppm), or 1,4-phenylenebis(methylene)selenocyanate (p-XSC) (5 ppm as selenium) as a positive control was fed to 6-week-old virgin female CD rats for 1 week before carcinogen treatment. Neither soy nor genistein affected the extent of DMBA-DNA binding in liver. In mammary tissue, 111 ppm genistein in the diet was more effective than the soy protein isolate, although the latter contains the same amount of genistein, mainly present as a glucoside conjugate. As shown before, p-XSC inhibited DMBA-DNA binding in mammary tissue. Total binding was inhibited because of reduced formation of three major adducts: anti-diol epoxide deoxyguanosine, syn-diol epoxide deoxyadenosine, and anti-diolepoxide deoxyadenosine. Thus, an additional experiment with 111 and 222 ppm of genistein was performed; 222 ppm genistein had a weaker effect than that observed for 111 ppm. Nevertheless, 111 ppm of genistein in the diet appears to inhibit the initiation phase of DMBA-induced rat mammary tumors and may partially account for the reported inhibitory effect of soy against DMBA-induced rat mammary tumors.