Retinoids induce cellular differentiation and inhibit cellular proliferation. Proliferation of human breast carcinoma cells in vitro is markedly inhibited by these compounds. On the other hand, insulin-like growth factors (IGFs) and their receptors seem to be involved in the growth of certain breast carcinoma cells by autocrine or paracrine effects. Since the effects of both IGF-I and IGF-II may be modulated by specific binding proteins (IGF-BPs) we examined the possibility that one mechanism by which retinoic acid may inhibit cancer growth is by an alteration in these BPs, thereby blocking IGF’s growth effect.Retinoic acid (RA; 1 µm) completely blocked the effect of IGF-I (50 ng/ml) on enhancing proliferation of MCF-7 cells in culture. This effect of RA was not associated with any significant change in specific IGF-I-binding sites on these cells. RA induced a 3-fold increase in IGF-binding activity in conditioned medium, measured using a polyethylene glycol-immunoglobulin precipitation assay and a charcoal absorption assay. This increase was associated with the appearance of 42- and 46-kDa IGF-BPs on ligand blotting. The effect of RA on these IGF-BPs was time and concentration dependent. In contrast, during some experiments the 27- and 36-kDa BPs actually decreased.These findings support the hypothesis that RA may inhibit the growth of certain breast carcinoma cells by increasing the secretion of certain IGF-BPs, which could directly modulate the growth effect of IGFs.