Earlier reports have indicated that patients with endometrial clear cell carcinoma (CCC) may have an increased risk for thromboembolic events. Tissue factor is a 47-Kd transmembrane glycoprotein that plays a critical role in platelet activation, fibrinogenesis, blood clot formation, and as such, general hemostasis. The mammalian heparanase is an endo-β-glucuronidase that can cleave heparan sulfate at specific molecular sites, resulting in structural modification of the extracellular matrix barrier, facilitating cancer cell invasion, and eventual metastasis. Recent reports indicate that heparanase may also induce tissue factor expression. The purpose of this study is to assess the clinicopathologic significance of tissue factor and heparanase expression, especially as they relate to the risk of thromboembolic events, in endometrial CCC and selected other endometrial cancers. Eighty-four endometrial carcinomas, including 17 CCC, 20 endometrial serous carcinomas, 15 grade 1 endometrial endometrioid carcinomas (EEC), 15 grade 2 EEC, 10 grade 3 EEC, and 7 mixed endometrial carcinomas with at least a 10% clear cell component (mixed CCC) were evaluated for the immunophenotypic expression of heparanase and tissue factor, and their associated frequency of thromboembolic events. Seven of the 84 patients experienced 8 thromboembolic events during the follow-up period. By multivariate analysis, the pure CCC histotype [odds ratio 5.2; 95% confidence interval (CI): 2.4523-13.6754; P=0.026] was significantly associated with an elevated risk for thromboembolic events. Tissue factor expression was present in 12 (14.28%) of the 84 endometrial carcinomas, including in 7 (41.17%) of 17 pure CCC, 2 (10%) of 20 endometrial serous carcinomas, 1 (14.3%) of 7 mixed CCC, 2 (13.3%) of 15 grade 1 EEC, and in 0% of grade 2 and 3 EEC. Tissue factor expression was significantly more likely to be seen in pure CCC than in all other cancers as a group (P=0.0018) and in all other high-grade endometrial cancers (P=0.007). By multivariate analysis, tissue factor expression was significantly associated with the risk of thromboembolic events [odds ratio 4.8 (95% CI: 1.9196-11.93), P=0.013]. Tissue factor expression was not associated with patient outcome or any other clinicopathologic parameter. Heparanase expression was present in 57 (67.8%) of the 84 endometrial carcinomas, and was significantly associated with the endometrioid histotype, but not outcome or the risk of thromboembolic events. For the overall group of all cancers, there was no significant correlation between heparanase and tissue factor expression (Spearman rank correlation, r=0.311, P=0.4). In summary, patients with endometrial CCC have an increased risk of developing thromboembolic events compared with patients with the other histotypes. This increased risk may be related, at least partially, to an increased rate of tissue factor expression in endometrial CCC.