Objectives: Frequent emergency department (ED) users are high-risk and high-resource-utilizing patients. This systematic review evaluates effectiveness of interventions targeting adult frequent ED users in reducing visit frequency and improving patient outcomes.Methods: An a priori protocol was published in PROSPERO. Two independent reviewers screened, selected, rated quality, and extracted data. Third-party adjudication resolved disagreements. Rate ratios of post-versus pre-intervention ED visits were calculated. Data sources were from a comprehensive search that included seven databases and the gray literature. Eligibility criteria for selecting studies included experimental studies assessing the effect of interventions on frequent users' ED visits and patient-oriented outcomes.Results: A total of 6,865 citations were identified and 31 studies included. Designs were noncontrolled (n = 21) and controlled (n = 4) before-after studies and randomized controlled trials (n = 6). Frequent user definitions varied considerably and risk of bias was moderate to high. Studies examined general frequent users or those with psychiatric comorbidities, chronic disease, or low socioeconomic status or the elderly. Interventions included case management (n = 18), care plans (n = 8), diversion strategies (n = 3), printout case notes (n = 1), and social work visits (n = 1). Post-versus pre-intervention rate ratios were calculated for 25 studies and indicated a significant visit decrease in 21 (84%) of these studies. The median rate ratio was 0.63 (interquartile range = 0.41 to 0.71), indicating that the general effect of the interventions described was to decrease ED visits post-intervention. Significant visit decreases were found for a majority of studies in subgroup analyses based on 6-or 12-month follow-up, definition thresholds, clinical frequent user subgroups, and intervention types. Studies reporting homelessness found consistent improvements in stable housing. Overall, interstudy heterogeneity was high. The authors have no potential conflicts to disclose. PROSPERO registration number CRD42014015058. Study group authorship: Jessica Moe conceptualized and drafted the protocol, screened abstracts and articles for inclusion, extracted data, analyzed data, and wrote the manuscript; Scott Kirkland helped to draft the protocol, screened abstracts and articles for inclusion, analyzed data, assessed study quality, and wrote sections of the manuscript; Erin Rawe drafted the protocol and extracted data; Maria Ospina helped to draft the protocol, assessed study quality, and provided third-party adjudication for inclusion screening and quality assessment; Ben Vandermeer helped to plan and perform the statistical analysis; Sandy Campbell developed and ran the search strategy; Brian H. Rowe conceptualized the protocol, provided third-party adjudication for inclusion screening and quality assessment, analyzed data, and wrote a section of the manuscript. All authors reviewed, edited, and approved the final manuscript. Existing evide...