Genistein, a soy isoflavone, has attracted much attention for its chemopreventive properties. Overexpression and constitutive activation of receptor tyrosine kinases are frequent events in human cancer. Because genistein has previously been reported to decrease HT-29 cell growth, the present study compared the effects of genistein with daidzein on the protein levels of the members of the ErbB receptor family and insulin-like growth factor-I (IGF-I) receptor (IGF-IR). HT-29 cells were cultured in serum-free medium, with 0, 25, 50, or 100 micromol/L genistein, daidzein, and/or 10 nmol/L IGF-I. DNA synthesis was estimated by 5-bromo-2'-deoxyuridine incorporation. Apoptotic cells were analyzed by annexin-V staining followed by flow cytometry. Genistein inhibited viable HT-29 cell numbers, in a dose-dependent manner, whereas daidzein had no effect on cell growth. The decrease in cell growth caused by genistein was due to decreased DNA synthesis and apoptosis induction. Immunoblot analysis showed that neither genistein nor daidzein decreased the protein levels of either of the epidermal growth factor receptors, ErbB2 or ErbB3. Genistein did, however, decrease the IGF-IR protein levels, whereas daidzein had no effect. Genistein did not change the protein levels of insulin-receptor substrate-1 (IRS-1), the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), or Akt. Immunoprecipitation/western blot analyses revealed that genistein decreased IGF-I-stimulated phosphorylation of IGF-IR and IRS-1, recruitment of p85 to IGF-IR, and phosphorylation of Akt. These results suggest that inhibition of cell proliferation and induction of apoptosis by genistein are mediated, at least in part, by its ability to inhibit IGF-IR signaling and the PI3K/Akt pathway.