Tissue factor (TF), the primary cellular initiator of the coagulation protease cascade, is implicated in having important roles in hemostasis, thrombogenesis, inflammation, and the cellular immune response, although the cytologic distribution of TF in tissues has yet to be described. This study used epitope-defined monoclonal antibodies to human tissue factor for immunohistochemical localization of TF in normal human tissues. TF was selectively expressed in tissues and was associated with cells rather than extracellular matrix. It was anatomically sequestered from blood, being undetectable in endothelium and peripheral blood cells. TF was present in vascular adventitia, organ capsules, epidermis, and mucosal epithelium. Most dermal and submucosal fibroblasts were negative. Except for alveolar macrophages and possibly dendritic cells of some lymphoid follicles, tissue macrophages did not express TF; (expression was demonstrable in LPS stimulated monocytes). Cerebral cortex, renal glomeruli, and cardiac myocytes were additional sites of prominent TF expression. Based on the cellular distribution of TF, it is hypothesized that intravascular initiation of coagulation requires induced expression by intravascular cells, and that the normal distribution of TF represents a hemostatic "envelope" ready to activate coagulation when vascular integrity is disrupted.