Tissue factor pathway inhibitor (TFPI) is the primary physiological inhibitor of tissue factor (TF) induced coagulation. Low plasma TFPI levels have been shown to be associated with increased risk of arterial and venous thrombosis. Several clinical studies have reported that single nucleotide polymorphisms (SNPs) in the regulatory regions of the gene, such as the -287T/C, the -399C/T, and the -33T/C SNPs, may affect plasma TFPI levels. However, molecular studies investigating the functionality of the polymorphisms are lacking. In this study, we found that the -287C and -399T alleles affected the activity of the promoter using a reporter gene system. This was also the case for the -33T/C polymorphism. An association regarding the transcriptional activity of the reporter gene was detected between the -287C allele and the -33T/C polymorphism. Analysis of the polymorphic sites with electrophoretic mobility shift assay (EMSA) showed that all three polymorphisms potentially alter DNA-protein interactions. Based on these findings, we speculate that the -287C and the -33C alleles can be associated with lowered risk of thrombosis. (C) 2010 Elsevier Inc. All rights reserved.