Abstract-The G20210A transition of the prothrombin gene has been identified as a common but probably mild hereditary risk factor for venous thromboembolism (VTE). However, the prothrombin gene variant might contribute to the penetrance of thromboembolic disease in many patients with other prothrombotic defects, such as the FV:R506Q mutation. In this investigation, the A20210 allele was found in 9 of 450 healthy controls (2%). Among 89 asymptomatic FV:Q 506 carriers, 3 subjects were doubly affected (3.4%). In contrast, of 263 unrelated carriers of the FV:Q 506 mutant with a history of juvenile VTE, 30 also had the prothrombin gene G20210A variant (11.4%), including 25 of 220 patients who were heterozygous (11.4%) and 5 of 43 homozygous (11.6%) for FV:Q 506 . Thus, the A20210 allele of the prothrombin gene is significantly overrepresented in symptomatic FV:Q 506 carriers compared with healthy controls (PϽ0.0001) and asymptomatic relatives carrying the FV mutant (Pϭ0.02). Persons homozygous for the 20210A allele were not found. A statistically significant increase in the prevalence of more unusual sites of venous thrombosis at clinical onset was found in doubly affected patients (9 of 30; 30%) compared with patients without the prothrombin gene variant (26 of 233; 11.1%) (Pϭ0.004). First VTE occurred spontaneously in 53.3% of all doubly affected patients (16 of 30) and in 28.3% of all simply affected patients (66 of 233) (Pϭ0.005). Among patients with VTE preceded by circumstantial risk factors, the A20210 allele was found in 7.7% (14 of 181). We conclude that the A20210 allele of the prothrombin gene is frequently coinherited in symptomatic FV:Q 506 carriers and possibly influences age, site, and type of thrombotic onset manifestation in these patients. Key Words: genes Ⅲ variation (genetics) Ⅲ prothrombin Ⅲ factor V Ⅲ mutation Ⅲ thrombosis, venous W ithin the last decade, several variant alleles of the genes encoding proteins regulating blood coagulation, such as protein C, protein S, antithrombin, and fibrinogen, have been shown to be relatively strong but uncommon risk factors for thrombosis. [1][2][3][4] Resistance to activated protein C due to the factor (F) V Arg 506 to Gln mutation (FV:R506Q) 5-7 is the most common inherited risk factor for venous thromboembolism (VTE) and has been found at an average prevalence of 22% (range, 20% to 52%) in patients with primary VTE. 1,8 -11 Furthermore, a novel sequence variation in the prothrombin (factor II) gene, which is encoded by a 21-kb-pair-long gene localized on chromosome 11 12 has recently been identified as another common risk factor for VTE. The genetic variation is located at nucleotide position 20210 in the 3Ј-untranslated region of the prothrombin gene at which 1 nucleotide is changed (G to A transition. 13 Carriers of the A20210 allele were found in 0% to 4% of healthy controls and in 5% to 19% of patients with VTE. [13][14][15][16][17][18] Whereas the cosegregation of the FV:R506Q mutation and other well-established thrombotic risk factors has been inves...