BACKGROUND AND OBJECTIVES: The purpose of this study was to assess the incidence of central venous catheter (CVC)-related thrombosis and the contribution of two common inherited coagulation disorders (factor V Leiden, prothrombin G20210A mutation) to this complication in a large hospital population. DESIGN AND METHODS: In a prospective setting, patients were assessed daily for signs and symptoms suggestive of thrombosis. Routine Doppler-ultrasound was performed weekly in all patients until CVC removal. Doppler-ultrasound examinations were stored on videotape and assessed by two blinded observers. In the case of clinically suspected thrombosis the physicians followed routine diagnostic and therapeutic procedures. The presence of factor V Leiden and prothrombin G20210A mutation and other potential risk factors were assessed in all patients. RESULTS: In 252 consecutive patients the cumulative incidence of-CVC related thrombosis was 30% (clinically manifested thrombosis: 7%). The relative risk of factor V Leiden or prothrombin G20210A mutation for thrombosis was 2.7 (CI95% 1.9 to 3.8). In addition, a personal history of venous thrombosis was associated with CVC-related thrombosis, whereas the severity of thrombosis was affected by the absence of anticoagulants and the presence of cancer. INTERPRETATION AND CONCLUSIONS: Thrombosis is frequently observed after central venous catheterization. Common inherited abnormalities in blood coagulation contribute substantially to CVC-related thrombosis. In view of physicians' reluctance to prescribe prophylactic anticoagulant treatment in vulnerable patients, a priori determination of common inherited and acquired risk factors may form a basis to guide these treatment decisions.