Simulation is a versatile technique used in a variety of health care settings for a variety of purposes, but the extent to which simulation may improve patient safety remains unknown. This systematic review examined evidence on the effects of simulation techniques on patient safety outcomes. PubMed and the Cochrane Library were searched from their beginning to 31 October 2012 to identify relevant studies. A single reviewer screened 913 abstracts and selected and abstracted data from 38 studies that reported outcomes during care of real patients after patient-, team-, or system-level simulation interventions. Studies varied widely in the quality of methodological design and description of simulation activities, but in general, simulation interventions improved the technical performance of individual clinicians and teams during critical events and complex procedures. Limited evidence suggested improvements in patient outcomes attributable to simulation exercises at the health system level. Future studies would benefit from standardized reporting of simulation components and identification of robust patient safety targets.