BACKGROUND Emergency department (ED) utilization has dramatically increased in developed countries over the last twenty years. Because it has been associated with adverse outcomes, increased costs, and an overload on the hospital organization, several policies have tried to curb this growing trend. The aim of this study is to systematically review the effectiveness of organizational interventions designed to reduce ED utilization. METHODOLOGY/PRINCIPAL FINDINGS We conducted electronic searches using free text and Medical Subject Headings on PubMed and The Cochrane Library to identify studies of ED visits, re-visits and mortality. We performed complementary searches of grey literature, manual searches and direct contacts with experts. We included studies that investigated the effectiveness of interventions designed to reduce ED visits and the following study designs: time series, cross-sectional, repeated cross-sectional, longitudinal, quasi-experimental studies, and randomized trial. We excluded studies on specific conditions, children and with no relevant outcomes (ED visits, re-visits or adverse events). From 2,348 potentially useful references, 48 satisfied the inclusion criteria. We classified the interventions in mutually exclusive categories: 1) Interventions addressing the supply and accessibility of services: 25 studies examined efforts to increase primary care physicians, centers, or hours of service; 2) Interventions addressing the demand for services: 6 studies examined educational interventions and 17 examined barrier interventions (gatekeeping or cost). CONCLUSIONS/SIGNIFICANCE The evidence suggests that interventions aimed at increasing primary care accessibility and ED cost-sharing are effective in reducing ED use. However, the rest of the interventions aimed at decreasing ED utilization showed contradictory results. Changes in health care policies require rigorous evaluation before being implemented since these can have a high impact on individual health and use of health care resources. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO. Identifier: CRD420111253.