One of the causes of portal hypertension is portal vein thrombosis (PVT). The aim of this study was to determine whether natural anticoagulant deficiencies, activated protein C resistance (APCR), and factor V Leiden play a role in the development of PVT, leading to cavernous transformation of the portal vein (CTPV). Twenty-three patients with idiopathic CTPV (group 1) seen at Hacettepe University Hospital during the past 12 years were identified and prospectively studied. These 23 patients underwent a detailed hematological evaluation including measurement of protein S, protein C, antithrombin III, activated protein C resistance (APCR), and factor V Leiden gene mutation. Additionally, all patients were tested for anticardiolipin antibodies (ACA), IgG, IgM, and lupus anticoagulant (LA). Natural anticoagulants and APCR were measured using available commercial kits, and factor V Leiden mutation (R506Q) was detected by Mnl I digestion of an amplified factor V DNA fragment. All parameters were measured at least 6 months after the diagnosis of CTPV was established. No patient was on anticoagulant or antiaggregant treatment while rested. The findings in these 23 patients were compared with those in 20 healthy control subjects (group 2), in whom all tests mentioned above were also performed. In 23 patients (group 1), who had no recognizable factor for portal vein thrombosis, considerably natural anticoagulant deficiencies and factor V Leiden mutation positivity were found when we compare them to those healthy controls (group 2). The protein C levels of six patients (26%), the protein S levels of 10 patients (43.5%), and the antithrombin III levels of five patients (26%) were lower than in control subjects. Two patients were found to have combined protein S and antithrombin III deficiency, and one had combined protein S and C deficiency and APCR. APCR was detected in seven of the 23 patients, and six of these seven patients were found to have R506Q factor V Leiden mutations. In group 1, ACA IgG levels were higher in four patients (17%) and ACA IgM level was higher in one (4%) compared with the control group. LA was positive in only one patient in group 1. Natural anticoagulant deficiencies and factor V Leiden mutation are strongly associated with PVT. The natural anticoagulant deficiencies and APCR (almost totally caused by R506Q mutation) produce a favorable medium for thrombus generation. PVT seems to be related to the natural anticoagulant deficiencies and factor V Leiden R506Q mutation. A combination of these defects increases the incidence of PVT and these factors should be evaluated carefully in patients with idiopathic CTPV.