Various human malignant tumors, including malignant melanoma, showed an absence of fibrinolytic activity by the histochemical fibrin slide method. In contrast, a tissue plasminogen activator has been isolated both from extracts of melanoma tissues and melanoma cell lines in culture, and has been characterized to be a potent plasminogen activator. In an attempt to resolve this apparent discrepancy, we studied biopsied specimens of melanoma and several melanoma cell lines by the immunoperoxidase method. Tissue plasminogen activator was observed in melanoma tissues and cell lines while the various inhibitors of fibrinolysis, including alpha 2-anti-plasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, and antithrombin III were found intracellularly only in the melanoma tumor cells, but not in melanoma cell lines. We believe that these inhibitors are derived from the blood and are bound to the tissue plasminogen activator within the melanoma cells. This hypothesis is supported by in vivo studies showing binding of tissue plasminogen activator in cultured cell lines to several inhibitors. Since these are potent inhibitors of fibrinolysis, their presence in tumor cells would explain the lack of fibrinolytic activity in melanoma tissues.