OBJECTIVES: To compare the relative effectiveness and safety of all stroke prevention agents in patients with atrial fibrillation (AF) through a systematic review and network meta-analyses. METHODS: A search of MEDLINE, EMBASE, and CENTRAL was conducted (through December 2013) to identify Phase III randomized controlled trials of AF patients, comparing any two of the following agents: placebo, aspirin, aspirin and clopidogrel combination therapy (A+C), adjusted-dose warfarin (target INR 2.0-3.0), dabigatran (110 mg and 150 mg), rivaroxaban, apixaban, and edoxaban (high and low doses). We conducted fixed-effects Bayesian network meta-analyses to generate relative effectiveness estimates for the outcomes of interest (all stroke, ischemic stroke, myocardial infarction, overall mortality, major bleeding, intracranial hemorrhage, and fatal bleeding). For each outcome, agents were ranked according to their likelihood of being the best option. RESULTS: We identified 12 studies, comprising 81,771 patients. Compared to warfarin, dabigatran 150 mg (RR 0.65, 95% CI 0.52-0.82) and apixaban (RR 0.80, 95% 0.66-0.96) reduced the risk of all strokes. Dabigatran 150 mg was also more effective than warfarin at reducing ischemic stroke risk (RR 0.77, 95% CI 0.59 – 0.99). All anticoagulants were more effective than A+C, aspirin and placebo at reducing the risk of ischemic and all strokes. All treatments were associated with a lower risk of major bleeding than warfarin, except for dabigatran 150 mg, rivaroxaban, A+C, and aspirin. Dabigatran 150 mg was most likely to be ranked best at reducing ischemic stroke risk, and low-dose edoxaban as best at reducing major bleeding risk. CONCLUSIONS: Anticoagulants effectively reduce the risk of ischemic and all strokes in AF patients, and are more effective than antiplatelets. Some novel anticoagulants are associated with lower stroke and/or major bleeding risk than warfarin. In addition to a drug’s safety and effectiveness, individual treatment should consider the patient’s underlying stroke and bleeding risk profile.