Tissue factor (TF) is the high-affinity receptor for plasma factors VII and VIIa. TF plays a role in normal hemostasis by initiating the cell-surface assembly and propagation of the coagulation protease cascade. Outside the vasculature, TF expression is highly dependent upon cell type. TF can also be induced by inflammatory mediators to appear on monocytes and vascular endothelial cells as a component of cellular immune responses. As an initial step toward elucidating the regulatory regions involved in control of TF gene expression, we have established the organization of the 12.4 kbp human TF gene and its complete DNA sequence. There are six exons separated by five introns. Within intron 5, we have mapped the single nucleotide difference which leads to the previously described MspI polymorphism; the same intron also contains an apparently polymorphic PstI site. The TF gene also contains three full-length Alu repeats and one partial Alu repeat. A single major transcription start site was identified 26 bp downstream from a TATA consensus promoter element. The putative promoter and first exon are located within a 1.2 kbp region of very high G + C content which fits the criteria of an HTF island. A cluster of predicted binding sites for a number of known transcription factors was found to coincide with this putative promoter region. These factors included AP-1 and AP-2 which can mediate the effects of phorbol esters, agonists known to induce TF expression in monocytes and vascular endothelial cells.