CG-5 estrogen-sensitive human breast cancer cells contain specific Epidermal Growth Factor receptors (EGF-R, Kd = 0.09-0.17 nM) and respond to the mitogenic effect of EGF. The increase in cell proliferation has been observed starting with very low concentrations of EGF (10-12M) and was statistically significant at all doses. Nevertheless, cell growth stimulation was emphasized when cells were grown under stringent culture conditions. When cells were exposed to 100 IU/ml of natural beta-interferon (n beta-IFN) the binding of EGF to the cell membrane was reduced after 72 hours of treatment, while the exposure of CG-5 cells to 1000 IU/ml of n beta-IFN resulted in an EGF-R reduction which started after 48 hours and became statistically significant after 72-120 hours. If CG-5 cells were treated with 1000 IU/ml of recombinant alpha 2b-interferon (ra2b-IFN) this reduction was observed after 168 hours of exposure to the drug. Both the IFNs abolished EGF-stimulated cell growth. Our results indicate that IFN treatment down-regulates EGF-R in estrogen-sensitive breast cancer cells and suggests that this down-regulation may be involved in the inhibitory action of IFN on cell growth.