The recruitment of phagocytic leukocytes to sites of vessel wall injury plays an important role in thrombus dissolution by proteases elaborated on their adhesion. However, leukocyte adhesion to the fibrin clot can be detrimental at the early stages of wound healing when hemostatic plug integrity is critical for preventing blood loss. Adhesion of circulating leukocytes to the insoluble fibrin(ogen) matrix is mediated by integrins and occurs in the presence of a high concentration of plasma fibrinogen. In this study, the possibility that soluble fibrinogen could protect fibrin from excessive adhesion of leukocytes was examined. Fibrinogen was a potent inhibitor of adhesion of U937 monocytoid cells and neutrophils to fibrin gel and immobilized fibrin(ogen). An investigation of the mechanism by which soluble fibrinogen exerts its influence on leukocyte adhesion indicated that it did not block integrins but rather associated with the fibrin(ogen) substrate. Consequently, leukocytes that engage fibrinogen molecules loosely bound to the surface of fibrin(ogen) matrix are not able to consolidate their grip on the substrate; subsequently, cells detach. This conclusion is based on the evidence obtained in adhesion studies using various cells and performed under static and flow conditions. These findings reveal a new role of fibrinogen in integrin-mediated leukocyte adhesion and suggest that this mechanism may protect the thrombus from premature dissolution.