Warfarin has had a thin margin of benefit over risk for the prevention of stroke and systemic embolism in patients with ESRD because of higher bleeding risks and complications of therapy. The successful use of warfarin has been dependent on the selection of patients with nonvalvular atrial fibrillation at relatively high risk of stroke and systemic embolism and lower risks of bleeding over the course of therapy. Without such selection strategies, broad use of warfarin has not proven to be beneficial to the broad population of patients with ESRD and nonvalvular atrial fibrillation. In a recent meta-analysis of use of warfarin in patients with nonvalvular atrial fibrillation and ESRD, warfarin had no effect on the risks of stroke (hazard ratio, 1.12; 95% confidence interval, 0.69 to 1.82; P=0.65) or mortality (hazard ratio, 0.96; 95% confidence interval, 0.81 to 1.13; P=0.60) but was associated with increased risk of major bleeding (hazard ratio, 1.30; 95% confidence interval, 1.08 to 1.56; P<0.01). In pivotal trials, novel oral anticoagulants were generally at least equal to warfarin for efficacy and safety in nonvalvular atrial fibrillation and mild to moderate renal impairment. Clinical data for ESRD are limited, because pivotal trials excluded such patients. Given the very high risk of stroke and systemic embolism and the early evidence of acceptable safety profiles of novel oral anticoagulants, we think that patients with ESRD should be considered for treatment with chronic anticoagulation provided that there is an acceptable bleeding profile. Apixaban is currently indicated in ESRD for this application and may be preferable to warfarin given the body of evidence for warfarin and its difficulty of use and attendant adverse events.