The present study aimed to determine whether four previously described polymorphisms found within the tissue factor pathway inhibitor (TFPI) gene are associated with free plasma TFPI levels or with TFPI activity as well as the risk of ischaemic stroke in stroke patients and control individuals. We conducted a case-control study of 162 first-ever ischaemic stroke cases and 170 randomly selected community control individuals. The TFPI genotype was determined for the T-287C, C-399T, Intron 7 C-33T, and Val264Met (G874A) polymorphisms. Free plasma TFPI and TFPI activity were measured during the first 7 days and 3-6 months after the acute stroke event. Free plasma TFPI levels were significantly lowered 3-6 months after stroke compared with levels observed in the patient group during the acute phase of the stroke (mean, 16.3 versus 22.46 ng/ml; P = 0.046) and among the control group (mean, 16.3 versus 22.79 ng/ml; P < 0.0001). Conversely, TFPI activity was significantly up-regulated during the acute phase (mean, 1.30 versus 1.11 U/ml; P = 0.0051) and remained elevated 3-6 months later (mean, 1.28 versus 1.11 U/ml; P = 0.03). The TFPI gene polymorphisms studied were not significantly associated with TFPI levels or activity, nor with the risk of ischaemic stroke. In conclusion, the TFPI activity and concentration in plasma varied significantly after an ischaemic stroke; however, these variations were not found to be due to the presence of any of the genetic mutations analysed in this study. Our results are consistent with the emerging model suggesting the lipoprotein-bound portion of TFPI has a significant influence on coagulation and diseases of haemostasis.