Lipoxins (LX) are eicosanoids generated via transcellular biosynthetic routes during inflammation, hypersensitivity reaction, and after angioplasty. LXs are modulators of leukocyte trafficking and vascular tone. Their influence on the coagulation cascade has not been determined. In this study, we evaluated the influence of LXs on the expression of tissue factor (TF), a key regulator of coagulation. TF activity was measured in lysates of monocytes, human umbilical vein endothelial cells, and ECV304 cells using a one-stage clotting assay. LXA₄ stimulated TF activity in each cell type. The influence of LXA₄ on TF activity by ECV304 cells was studied further to explore the mechanism of induction of TF expression. LXA₄-induced TF activity was dose dependent, cycloheximide sensitive, and associated with increased TF mRNA levels. Induction of TF activity was specific for LXA₄ and was not observed with LXB₄, the other major lipoxin generated by mammalian cells. Furthermore, ECV304 cell TF expression was not influenced by 15(R/S)-methyl-LXA₄ or 16-phenoxy-LXA₄, synthetic analogs of LXA₄ that activate the myeloid LXA₄ receptor, and was not modulated by SKF-104353, which blocks LXA₄ bioactivities transduced through the putative shared LXA₄/LTD₄ receptor. LXA₄-stimulated TF expression was blunted by pertussis toxin and by GF-109203X, an inhibitor of protein kinase C, and was not associated with degradation of IB. Our results establish that LXA₄ induces TF activity via cell signaling pathways with different structural and receptor requirements from those described for inhibition of leukocyte-endothelial cell interactions. They suggest a role for LXA₄ as a modulator of TF-related vascular events during inflammation and thrombosis.