The adhesive interaction between tumor cells, host cells or extracellular matrix (ECM) plays a crucial role in metastatic formation. We used synthetic polypeptide containing a repetitive core sequence, Arg-Gly-Asp (RGD), of cell-adhesive molecules; poly (RGD), to antagonize the adhesive interaction between ECM and integrin receptors on tumor cell surface during the metastatic cascade. Poly (RGD) significantly inhibited the experimental lung and liver metastasis as compared with RGD peptide when it was coinjected i.v. with different types of tumors. In a spontaneous lung metastasis model using B16-BL6 melanoma, multiple i.v. administrations of poly (RGD), before or after surgical excision of the primary tumor, resulted in significant reduction of the lung colonization. The mechanism responsible for the inhibition is partly associated with the ability to interfere with cell functions such as adhesiveness, motility, and invasiveness in the metastatic process. Poly (RGD) showed no cytotoxicity against host and tumor cells. Thus, the regulation of adhesive interaction of tumor cells with ECM or host cells by anti-adhesive polypeptides may provide a promising approach for the prevention of tumor metastasis.