In a dose-finding study, the authors tested the administration of 4 fixed doses of oral ximelagtran twice daily starting after elective total knee replacement as prophylaxis against venous thromboembolism and compared the most effective ximelagatran dose with 30 mg of enoxaparin sodium subcutaneously twice daily starting 12 to 24 hours after surgery. The 6- to 12-day rates of overall venous thromboembolism (and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-, 18-, and 24-mg doses of ximelagatran twice daily were 27% (6.6%), 19.8% (2.0%), 28.7% (5.8%), and 15.8% (3.2%), respectively. The rates of overall venous thromboembolism (22.7%) and proximal deep vein thrombosis or pulmonary embolism (3.1%) for enoxaparin did not differ significantly compared with the 24-mg dose of ximelagatran twice daily (overall difference, −6.9%; 95% confidence interval, −18.0% to 4.2%; P = .3). There was no major bleeding with 24 mg of ximelagatran twice daily. Fixed dose, unmonitored ximelagatran, 24 mg twice daily, starting after surgery seems to be safe and effective oral prophylaxis against venous thromboembolism after total knee replacement.