Background-Tissue factor (TF), the surface receptor for the serine protease factor VIIa (FVIIa) and the initiator of the extrinsic coagulation cascade, supports vessel development and tumor metastasis by activation of extracellular, protease-dependent signaling pathways. The molecular mechanisms that do not require proteolytic activity of FVIIa are not yet known. The aim of the study, therefore, was to investigate the effects of active-site-inhibited FVIIa (FFR-FVIIa) on TF-mediated signaling. Methods and Results-After stimulation with FVIIa and FFR-FVIIa, migration and activation of the GTPase Rac (Rac1) or the mitogen-activated protein kinase p38 (p38) were analyzed in J82 cells. FVIIa and FFR-FVIIa stimulated migration and activation of Rac1 and p38 in a TF-specific, dose-and time-dependent manner. Enhancement of migration required activation of Rac1 and p38, because it was abolished after inhibition with SB203580 or overexpression of dominant negative p38 and Rac1. The cytoplasmic domain of TF was necessary because no effects of FFR-FVIIa could be detected after transfection of a TF deletion mutant lacking the cytoplasmic domain. Conclusions-We