BACKGROUND: New oral anticoagulants (NOACs), including direct thrombin inhibitors (DTIs) and factor Xa (FXa) inhibitors, are emerging alternatives for prophylaxis and treatment of atrial fibrillation (AF) and venous thromboembolism (VTE). PURPOSE: To compare the benefits and harms of NOACs versus warfarin for AF and VTE. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from January 2001 through July 2012; U.S. Food and Drug Administration (FDA) database for adverse event reports. STUDY SELECTION: English-language, randomized, controlled trials (RCTs) comparing NOACs with warfarin for management of AF or VTE and observational studies and FDA reports on adverse effects. DATA EXTRACTION: Two independent reviewers abstracted data and rated study quality and strength of evidence. DATA SYNTHESIS: Six good-quality RCTs compared NOACs (2 DTI studies, 4 FXa inhibitor studies) with warfarin. In AF, NOACs decreased all-cause mortality (risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]); in VTE, NOACs did not differ for mortality or VTE outcomes. Across indications, adverse effects of NOACs compared with warfarin were fatal bleeding (RR, 0.60 [CI, 0.46 to 0.77]), major bleeding (RR, 0.80 [CI, 0.63 to 1.01]), gastrointestinal bleeding (RR, 1.30 [CI, 0.97 to 1.73]), and discontinuation due to adverse events (RR, 1.23 [CI, 1.05 to 1.44]). Subgroup analyses suggest a higher risk for myocardial infarction with DTIs than with FXa inhibitors. Bleeding risk for NOACs may be increased in persons older than 75 years or those receiving warfarin who have good control. LIMITATION: There were no head-to-head comparisons of NOACs and limited data on harms. CONCLUSION: New oral anticoagulants are a viable option for patients receiving long-term anticoagulation. Treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment. PRIMARY FUNDING SOURCE: Department of Veterans Affairs.