Summary. Background: Recombinant human soluble thrombomodulin (ART-123) is composed of the active, extracellular, domain of thrombomodulin. ART-123 binds to thrombin and this complex converts protein C into the natural anticoagulant activated protein C. This study was performed to identify an effective and safe dose of ART-123 for prevention of venous thromboembolism after elective, unilateral total hip replacement. Methods and results: An open-label, sequential, dose-ranging study was performed in which 312 patients received either 0.3 mg kg−1 or 0.45 mg kg−1 of ART-123, subcutaneously, 2–4 h after surgery (day 1). Those who received 0.3 mg kg−1 were given a second dose of 0.3 mg kg−1 on day 6, and the first 29 of these patients also used intermittent pneumatic compression devices. Those who received 0.45 mg kg−1 were not given a second dose. Primary efficacy outcome was all deep vein thrombosis on mandatory bilateral venography performed on day 9 ± 2 and symptomatic venous thromboembolism up to day 11. Primary safety outcome was major bleeding up to day 11. Among patients who did not use intermittent pneumatic compression, venous thromboembolism occurred in 3.4% of 116 evaluable patients in the 0.3 mg kg−1 group and 0.9% of 111 patients in the 0.45 mg kg−1 group. Major bleeding occurred in 1.4% of 139 patients in the 0.3 mg kg−1 group and 6.3% of 144 patients in the 0.45 mg kg−1 group. Conclusion: ART-123 is a highly effective antithrombotic agent that should be directly compared with current methods of prophylaxis in patients who have major orthopedic surgery.