We have recently demonstrated that exposure of MCF7 cells to antiestrogens in vitro results in both accumulation of IGF-BP3 in media and reduced mitogenic responsivity to IGFs (Cancer Res. 53:5193-5198). We show here that MCF7 cell proliferation in steroid-stripped, serum containing media is significantly attenuated by rhIGF-BP3 (p < 0.05), with a maximal 40% inhibition of serum stimulated growth achieved by 6.25nM IGF-BP3. 10(-10) M estradiol (E2) significantly stimulated MCF7 proliferation, and co-incubation of estrogen containing cultures with 50nM IGF-BP3 resulted in significant attenuation of the estrogen-stimulated proliferation ([3H]thymidine incorporation: E2, 147 +/- 18% of control; E2 +/- IGF-BP3, 111 +/- 18% of control, p < 0.05). These results demonstrate antagonism of steroid stimulated proliferation by an IGF binding protein and are compatible with the hypothesis that antiestrogen-induced accumulation of IGF-BP3 in the conditioned media of MCF7 cells contributes to the cytostatic action of these drugs.