Fondaparinux, indirect factor Xa (FXa) inhibitor, is recommended for thromboprophylaxis for high-risk patients undergoing major orthopedic surgery. We evaluated the prothrombotic state and anticoagulant intensity of fondaparinux (2.5 mg daily) after total hip replacement (THR). Twenty patients underwent THR - seven bilateral and 13 unilateral. Blood samples were collected preoperatively and at 6 h, 8 h (2 h after fondaparinux), 1 day (12-14 h after fondaparinux), and 4 weeks (12-14 h after fondaparinux) postoperatively. Antithrombin (AT), fibrinogen, factor VIII activity, coagulation times, thrombin-AT (TAT) complex, D-dimer, C-reactive protein, prothrombinase-induced clotting time (PiCT) and anti-Xa activity were measured. The latter two were also tested after plasma spiking with fondaparinux 0-1.25 μg/ml. In spiked prophylactic fondaparinux samples (0-0.25 μg/ml), PiCT and anti-Xa activity correlated (r = 0.84) better than in the patient samples (r = 0.35). On the first day, anti-Xa activity and PiCT dissociated, and PiCT lost sensitivity for fondaparinux. AT decreased but stayed within the normal range, whereas TAT complex and D-dimer peaked at 6 h as signs of thrombin generation. On the first postoperative day, TAT and D-dimer halved. Bilateral THR associated with higher TAT and D-dimer levels up to 4 weeks. Perioperative FVIII levels were not affected, but were elevated in both groups (range 191-211%) after 4 weeks. Anti-Xa activity detected prophylactic fondaparinux with higher sensitivity than PiCT in vitro, but even more so in vivo. Thus, PiCT is not the method of choice to assess fondaparinux at least in association with THR. THR, bilateral more than unilateral, increased thrombin generation and D-dimer 7-11-fold early after surgery. Factor VIII activity and D-dimer remained elevated even after 4 weeks despite the compliant thromboprophylaxis with fondaparinux.