The mechanism by which transitional tumor cells adhere to areas of urothelial injury and the means by which heparin prevents this phenomenon were studied. Scanning electron microscopy and a radiolabeled tumor cell adherence assay were used to assess the activity of heparin and a "nonglycosaminoglycan" thrombolytic agent, recombinant tissue plasminogen activator, in preventing tumor cell adherence to areas of urothelial injury. Systemically administered heparin and intravesical therapy with recombinant tissue plasminogen activator duplicated the activity of intravesical heparin. Scanning electron microscopy showed tumor cells entrapped at the injury surface in a RBC/fibrin clot, which was prevented by intravesical heparin. These data suggest that clotting cascade activation by urothelial injury is the mechanism by which particulate adherence to the urothelium occurs. Interruption of this process by local or systemic anticoagulation with heparin or shifting of the equilibrium of clot formation/lysis toward thrombolysis with recombinant tissue plasminogen activator prevents tumor cell adherence. Intravesical thrombolytic therapy may represent a new approach to recurrence prophylaxis for superficial bladder carcinoma.