The tissue factor (TF) coagulation pathway is initiated when circulating factor (F)VII(a) encounters TF, a cell surface glycoprotein, as a result of vascular injury or pathological perturbation. TF-induced coagulation plays a primary role in hemostasis and also in the pathogenesis of various thrombotic disorders. Recent studies suggest that activation of the TF-pathway may also contribute to other pathophysiological processes by altering intracellular responses, either directly or via activated factor X (FXa) and thrombin generation. Therefore, suppression of the aberrant expression of TF/FVIIa on cell surfaces not only prevents thrombotic disorders but may also provide other protective effects. Recent ex-vivo and in-vivo experiments document the effectiveness of active site-blocked activated factor VII (FVIIai) in inhibiting TF-mediated injury. It is generally believed that FVIIai exerts its effects by limiting the formation of functional TF/FVIIa complexes by directly competing with plasma FVII(a) for limited available TF sites on cell surfaces. Although such competition can explain the effectiveness of FVIIai immediately after administration, it is not clear how it exerts its prolonged effects. In this manuscript, we summarize the use of FVIIai as an antithrombotic agent in various model systems and discuss potential mechanisms by which FVIIai may exert protective effects.