The mesothelial lining of the pleura and malignant mesothelioma promote fibrin deposition in pleural injury or neoplasia via expression of tissue factor (TF). It was hypothesized that these cells might also regulate intrapleural coagulation by elaborating TF pathway inhibitor (TFPI). TFPI activity and antigen in pleural fluids were assayed from patients with congestive heart failure (CHF), pneumonia, empyema, metastatic pleural cancer and malignant mesothelioma. The authors also assessed expression of TF and TFPI messenger ribonucleic acid (mRNA) as well as TFPI activity and antigen by human pleural mesothelial cells, malignant mesothelioma cells (MS-1 cell line) and human lung fibroblasts. Immunohistochemical analyses of normal, fibrotic, and neoplastic pleura were performed to determine whether TFPI antigen was expressed in vivo. The study revealed that TFPI was present in transudates from patients with CHF and exudative pleural effusions from patients with pneumonia, empyema or pleural carcinoma. TFPI mRNA, activity and antigen were expressed by pleural mesothelial cells, MS-1 cells and lung fibroblasts. Cytokines and serum stimulated a significant early increase in TF mRNA levels with minimal enhancement of TFPI mRNA, activity and antigen levels. TFPI antigen was found in normal, fibrotic and neoplastic pleural tissues. The current observations indicate that tissue factor pathway inhibitor is locally expressed in pleural disease, but that it does not prevent the development of a prothrombotic environment favouring local fibrin deposition in pleural inflammation or cancer.