Current guidelines recommend a target international normalized ratio (INR) range of 2.5 to 3.5 in patients with a mechanical mitral prosthesis. The Prospective Randomized On-X Anticoagulation Clinical Trial (PROACT) Mitral randomized controlled noninferiority trial assessed safety and efficacy of warfarin at doses lower than currently recommended, in patients with an On-X mechanical mitral valve.After On-X mechanical mitral valve replacement followed by at least 3 months of standard anticoagulation, 401 patients at 44 North American centers were randomized to low-dose warfarin (target INR 2.0 to 2.5) or standard-dose warfarin (target INR 2.5 to 3.5). All patients were prescribed aspirin 81 mg daily and encouraged to use home INR testing. The primary endpoint was the sum of the linearized rates of thromboembolism, valve thrombosis, and bleeding events. The design was based on an expected 7.3% event rate and 1.5% noninferiority margin.Mean patient follow-up was 4.1 years. Mean INR was 2.47 and 2.92 (P.001) in the low-dose and standard-dose warfarin groups, respectively. Primary endpoint rates were 11.9%/patient-year in the low-dose group and 12.0%/patient-year in the standard-dose group (difference -0.07, 95% confidence intervals: -3.40, 3.26). The confidence interval exceeded 1.5%, thus noninferiority was not achieved. Rates (%/patient-year) of the individual components of the primary endpoint were 2.3% vs 2.5% for thromboembolism, 0.5% vs 0.5% for valve thrombosis, and 9.13% vs 9.04% for bleeding.Compared to standard-dose warfarin, low-dose warfarin did not achieve noninferiority for the composite primary endpoint. (PROACT Clinicaltrials.gov number, NCT00291525).