Scant information exists on the role of thrombophilia in extrahepatic portal vein obstruction (EHPVO). We studied 65 patients with EHPVO, 500 with deep vein thrombosis (DVT) of the lower limbs, and 700 healthy controls referred for throm bophilia screening, including the search for gain- of- function mutations in g enes encoding coagulation factor V(factor V Leiden) and prothrombin (prothrombin G20210A); antithrombin, protein C, and protein S deficiency; and hyperhomocyste inemia. At least one abnormality in the thrombophilia screening was found in 40 % of patients with either EHPVO or lower limb DVT and in 13% of controls, fo r odds ratios of 4.0 (95% CI, 2.3- 7.0) and 4.4 (95% CI, 3.3- 5.9), respec tively. Statistically significant associations with EHPVO were observed for the prothrombin G20210A mutation (odds ratio, 8.1; 95% CI, 3.8- 17.5) and the def iciencies of antithrombin, protein C, or protein S taken together (odds ratio, 4 .5; 95% CI, 1.1- 18.0). The odds ratio for the prothrombin G20210A was approximately twice that for lower limb DVT. Patients with factor V Leiden had an odds ratio for EHPVO of 0.8 (95% CI, 0.1- 6.4) and for lower limb DVT of 7.5 (95% CI, 4.4- 13.0). The odds ratio for EHPVO in patients wit h hyperhomocysteinemia was 2.0 (95% CI, 0.9- 4.9). At variance with lower lim b DVT, oral contraceptive use was not associated with an increased risk of EHPVO . Myeloproliferative disorders were diagnosed in 35% of patients with EHPVO. I n conclusion, the risk for EHPVO is increased in the presence of thrombophilia r esulting from the prothrombin G20210A mutation and from the deficiencies of the naturally occurring anticoagulant proteins, but not from factor V Leiden. Scat information exists on the role of thrombophilia in extrahepatic portal vein obstruction (EHPVO). We studied 65 patients with EHPVO, 500 with deep vein thrombosis (DVT) of the lower limbs, and 700 healthy controls referred to for throm bophilia screening, including the search for gain-of-function mutations in g enes encoding coagulation factor V (factor V Leiden) and prothrombin (prothrombin G20210A); antithrombin, protein C, and protein S deficiency; and hyperhomocyste inemia. At least one abnormality in the thrombophilia screening was found in 40% of patients with either EHPVO or lower limb DVT and in 13% of controls, fo odds ratios of 4.0 (95% CI, 2.3-7.0) and 4.4 (95% CI, 3.3-5.9) respec tively. Statistically significant associations with EHPVO were observed for the prothrombin G20210A mutation (odds ratio, 8.1; 95% CI, 3.8-17.5) and the def iciencies of antithrombin, protein C, or protein S taken together (odds ratio, 4.5; 95% CI, 1.1-18.0). The odds ratio for the prot Patients with factor V Leiden had an odds ratio for EHPVO of 0.8 (95% CI, 0.1- 6.4) and for lower limb DVT of 7.5 (95% CI, 4.4-13.0). The odds ratio for EHPVO in patients wit h hyperhomocysteinemia was 2.0 (95% CI, 0.9-4.9). At variance with lower lim b DVT, oral contraceptive use was not associated with increased risk of EHPVO. Myeloproliferative disorders were diagnosed in 35% of patients with EHPVO. I n conclusion, the risk for EHPVO is increased in the presence of thrombophilia r esulting from the prothrombin G20210A mutation and from the deficiencies of the naturally occurring anticoagulant proteins, but not from factor V Leiden.