Inhibition of factor Xa (FXa) may interrupt thrombus progression. This study compared the antithrombotic activity of a novel FXa inhibitor, ZK-807834 [MW, 527 D; K i (human FXa), 0.11 nM], with recombinant tick anticoagulant peptide [rTAP; MW, 6,685 D; K i,(human FXa)= 0.28 nM], and DX-9065a [MW 445 D, K i (human FXa), 40 nM] in rabbits with arterial thrombosis induced by electrical vascular injury. ZK-807834 also was compared with low molecular weight heparin (LMWH; MW, 5,500 D) during venous thrombosis induced by placing a copper wire and threads in the vena cava. Inhibitors were administered as an iv bolus and 2-h infusion. Total dosages of ZK-807834,≥ 0.7 μmol/kg (n= 18); rTAP,≥ 1 μmol/kg (n= 18); or DX-9065a,≥ 11 μmol/kg (n= 18) decreased the incidence of arterial thrombotic occlusion compared with control animals (p< 0.05). However, five of six animals given the lowest effective dosage of rTAP and four of six animals given DX-9065a bled from a surgical incision> 5 min, but only two of six animals given ZK-807834 bled> 5 min. Venous clot weights were reduced compared with controls for dosages of ZK-807834≥ 0.007 μmol/kg (n= 36) or LMWH≥ 0.2 μmol/kg (n= 18). Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were unchanged from baseline at the minimally effective dose of ZK-807834, whereas aPTT was increased twofold at the effective dose of LMWH. Thus ZK-807834 may be useful to attenuate thrombosis at lower dosages and with less perturbation of systemic hemostasis compared with available agents.