We investigated the role of frequent fibrinogen polymorphisms in venous thromboembolic disease in conjunction with inherited thrombophilia. Two hundred unrelated subjects, all carriers of the factor V R506Q mutation (FV Leiden), were genotyped at the fibrinogen gene cluster. Among these subjects, 100 had experienced previous venous thromboembolism (VTE) and 100 were still asymptomatic for VTE. Significant differences were observed between the groups for the BclI polymorphism (P = 0.004). Scanning, by sequencing the DNA regions flanking the BclI marker, revealed new polymorphisms, a C to T transition and a G to T transversion at 1520 and 3369 base pairs 3' to the beta gene stop codon respectively. These markers showed less association with the clinical phenotype than BclI itself. A combined genotype including 10 markers was more frequent among the asymptomatic subjects (17%) than among patients (3%), and was associated with a reduction in fibrinogen antigen level (2.42 +/- 0.35 vs 2.69 +/- 0.41 g/l, P = 0.028) among the asymptomatic subjects. Our data suggest that, in the presence of inherited thrombophilia, frequent fibrinogen polymorphisms may interact to modulate the risk of venous thromboembolism.