Data in the literature on the prevalence of hereditary deficiency of the natural coagulation inhibitors are conflicting. We conducted a prospective study on 680 consecutive patients with a history of venous thrombosis to determine the prevalence of hereditary deficiency of antithrombin III (AT III), protein C (PC) and protein S (PS) and to establish selection criteria for rational patient screening. The mean age of the patients at investigation was 44.3 ± 15.4 years, while that at the first thrombotic event was 38.5 ± 14.8 years. The total prevalence of inhibitor deficiency states was 48/680 (7.1%). 19/680 patients (2.8%) had AT III-deficiency, 17 (2.5%) PC-deficiency, nine (1.3%) PS-deficiency and three (0.4%) a combined deficiency. In 37/48 deficient patients family studies were performed and the hereditary nature was established in 19 cases (2.8% of total patient population, six with AT III-deficiency, eight with PC-deficiency, four with PS-deficiency and one with a combined deficiency). Family studies in these 19 patients revealed 46 additional individual patients with a hereditary deficiency state. A positive family history was found in 15/19 (79%) with a proven hereditary deficiency state, in 153/619 (25%) of non-deficient patients and in 11/29 (38%) of deficient patients without established hereditary nature. The mean age at the first thrombotic event was significantly lower in patients with a hereditary deficiency state (26.8 years) compared with the other two groups (39.0 and 39.7 years, respectively). In all patients with a hereditary deficiency the first thrombotic event occurred before the age of 45 years. The site of thrombosis and the frequency of spontaneous and recurrent thromboembolic events was similar in patients with and without a deficiency state. We conclude that the prevalence of the hereditary deficiency of AT III, PC or PS in patients with a history of venous thrombosis or pulmonary embolism is low. A positive family history and the occurrence of the first thrombotic event at an early age are of predictive value for the presence of a hereditary deficiency state. These criteria are useful for selecting patients for determination of AT III, PC and PS.