Tumor cell metastasis is a complex process that depends in part on tumor cell adhesion to components of basement membranes and the extracellular matrix. Previous studies have indicated that the experimental metastasis of murine melanoma cells can be inhibited by ex vivo pretreatment of cells with purified adhesion-promoting fragments of laminin or the synthetic peptide arginyl-glycyl-aspartyl-serine (RGDS) prior to tail vein injection. This study extended the earlier reports to demonstrate that adhesion-promoting fragments of laminin and fibronectin can inhibit the metastasis of a tumor of different histologic origin, such as murine fibrosarcoma cells. Furthermore, ex vivo pretreatment of cells with a purified 33-kDa heparin-binding fragment of fibronectin, which promotes tumor cell adhesion by an RGDS-independent mechanism, was effective at inhibiting experimental melanoma and fibrosarcoma pulmonary metastases. The survival rate of animals receiving tumor cells pretreated with this fragment was significantly enhanced relative to control groups. As with previous studies, the mechanism of inhibition appeared to involve an increased clearance rate of tumor cells from the pulmonary microcirculation. These results suggest a role for cell surface proteoglycans in the adhesion and metastasis of certain malignant neoplasms. Furthermore, this study emphasizes the complexity of tumor metastasis and suggests that multiple strategies may be developed to inhibit hematogenous metastasis formation.