Background— Atrial fibrillation is an important cause of cardioembolic stroke. Oral anticoagulants (OAC) reduce stroke risk but increase the risk of serious bleeding. Left atrial appendage (LAA) procedures have been developed to isolate the LAA from circulating blood flow, as an alternative to OAC. We conducted a systematic review of the benefits and harms of surgical and percutaneous LAA exclusion procedures. Methods and Results— We searched multiple data sources, including Ovid MEDLINE, Cochrane, and Embase, through January 7, 2015. Of 2567 citations, 20 primary studies met prespecified inclusion criteria. We abstracted data on patient characteristics, stroke, mortality, and adverse effects. We assessed study quality and graded the strength of evidence using published criteria. Trials found low-strength evidence that percutaneous LAA exclusion confers similar risks of stroke and mortality as continued OAC, but this evidence was limited to the Watchman device in patients eligible for long-term OAC. Observational studies found moderate-strength evidence of serious harms with a variety of percutaneous LAA procedures. There is low-strength evidence that surgical LAA exclusion does not add significant harm during heart surgery for another indication, but evidence on stroke reduction is insufficient. Conclusions— There is limited evidence that the Watchman device may be noninferior to long-term OAC in selected patients. Data on effectiveness of LAA exclusion devices is lacking in patients ineligible for long-term OAC. Percutaneous LAA devices are associated with high rates of procedure-related harms. Although surgical LAA exclusion during heart surgery does not seem to add incremental harm, there is insufficient evidence of benefit.