INTRODUCTION: Fibrinogen Aalpha-Thr312Ala and Factor XIII Val34Leu polymorphisms have been shown to modify fibrin clot structure and function. However, clinical studies have yielded conflicting results on their possible association with venous thromboembolism (VTE). METHODS: We studied the association between these two polymorphisms and VTE in a hospital-based case-control study. We also assessed whether an independent or interactive association exists between Aalpha-fibrinogen Thr312Ala and FXIII Val34Leu polymorphisms and VTE. Fibrinogen Aalpha-Thr312Ala and FXIII Val34Leu polymorphisms were determined after PCR and restriction endonuclease digestion in 286 patients with idiopathic VTE and 286 age- and gender-matched controls. Results were analysed using a conditional logistic regression model for matched series. RESULTS: The Fg-Aalpha 312Ala allele was associated with higher risk of VTE (OR 1.5; 95% CI: 1.1 to 2.2, p=0.01) while the FXIII 34Leu allele appeared protective (OR 0.7; 95% CI: 0.6 to 0.9, p=0.02). Both alleles demonstrated an independent association with idiopathic VTE after adjustment for Factor V Leiden and G20210A prothrombin polymorphisms. There was no interaction between the fibrinogen Aalpha-Thr312Ala and FXIII Val34Leu polymorphisms for the risk of VTE. CONCLUSION: In this case-control study, the fibrinogen Fg-Aalpha 312Ala allele was associated with an increased risk of VTE. The FXIII 34Leu allele was also significantly associated with a lower risk of VTE without any interaction between the two polymorphisms studied.