In vitro thrombin generation, which reflects an individual's plasma coagulation potential and has been shown to correlate with the risk of venous thromboembolism (VTE), might represent a useful intermediate phenotype for the genetic dissection of VTE. As a proof of principle, we have investigated whether the thrombin generation assay can detect changes in the haemostatic balance associated with common genetic variation affecting the level or function of coagulation factors and inhibitors. The study population consisted of 140 healthy individuals. Plasma levels of coagulation factors and inhibitors and thrombin generation parameters determined at low tissue factor (TF) + or - thrombomodulin (TM) and at high TF + or - activated protein C (APC) were available from a previous study. All individuals were genotyped for F5 Leiden, F2 G20210A and 19 additional single nucleotide polymorphisms (SNPs) in haemostasis-related genes. The association of each SNP with plasma levels of the corresponding proteins and with thrombin generation parameters (lag time, peak height and endogenous thrombin potential [ETP]) was evaluated by statistical analysis. Not only F5 Leiden and F2 G20210A, but also several other common SNPs, significantly affected thrombin generation parameters. In particular, FGA A1069G (Thr312Ala) decreased the ETP(-APC), F2 A19911G increased the ETP(-APC), F10 IVS2 C+517G decreased the ETP(+APC), F12 C-46T decreased peak height at low TF, and TFPI T-287C and TFPI IVS7 T-33C decreased the ETP(+APC). These results indicate that the thrombin generation assay is sensitive to genetic variation in haemostasis-related genes, which makes it a promising tool to identify novel genetic risk factors of VTE.