Vegetarian populations show a decreased occurrence of breast, colon, and prostatic cancers. Epidemiological studies have identified seeds (maize, corn, and beans) as protective agents in these cancers. We have selected to study one abundant component of all seeds, protease inhibitors. Synthetic and natural protease inhibitors have been shown to inhibit tumor promotion in vivo and in vitro. In the present study, we report that a typical, natural protease inhibitor, the Bowman-Birk inhibitor isolated from soybeans, survives inactivation by stomach digestion in rodents and appears to be fully active as a protease inhibitor in the small intestine, where it complexes with the proteases occurring there, i.e., trypsin and chymotrypsin. A large part of the inhibitor is excreted as protease:protease inhibitor complexed in the feces. We also report the specific inhibition of transformation caused by ionizing radiation by this protease inhibitor. The mechanism of anticarcinogenesis of ingested protease inhibitors may involve the indirect effect of partially blocking protein absorption. High-protein and high-fat diets are known to increase cancer occurrence. Protease inhibitors reaching specific sites also have anticarcinogenic activities, as demonstrated by the radioprotective effect of a protease inhibitor in vitro. The relative importance of the indirect and direct action of protease inhibitors remains to be established.