The aim of the present study was to investigate the efficacy of three different parenterally administered anticoagulants for the prevention of thrombus formation on artificial heart valves in an experimental rabbit model. Unfractionated heparin was administered intravenously in group I (n = 10), Enoxaparin subcutaneously in group II (n = 10), fondaparinux intravenously in group III (n = 10), and no medication was administered to group IV (n = 9). Leaflets from Sulzer Carbomedics bileaflet mechanical heart valves were placed in a flow chamber. The flow chamber was filled with blood in a continuous circulation between the carotid artery and the jugular vein. In group IV the flow chamber was clotted after a median of 15 minutes of circulation. Weight analysis before and after 1 h of perfusion showed that the median thrombus weight was 18.0 mg in group I, 17.7 mg in group II, 20.3 mg in group III, and 30.8 mg in group IV. Further analysis by electron microscopy showed similar results regarding deposition of fibrin, platelets, and erythrocytes on leaflet surfaces. Fondaparinux and subcutaneously administered enoxaparin were as effective as intravenously administered unfractionated heparin in preventing thrombus formation on artificial heart valve leaflets in our investigation. This rabbit model, in which the heart valve leaflets were exposed to rabbit blood for a short time under laminar flow, should be further evaluated with respect to whether it can provide information about anti-thrombotic regimens in patients after mechanical heart valve replacement.