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Overuse of antibiotics in ambulatory care persists despite many efforts to address this problem. We performed a systematic review and quantitative analysis to assess the effectiveness of quality improvement (QI) strategies to reduce antibiotic prescribing for acute outpatient illnesses for which antibiotics are often inappropriately prescribed.We searched the Cochrane Collaboration's Effective Practice and Organisation of Care database, supplemented by MEDLINE and manual review of article bibliographies. We included randomized trials, controlled before-after studies, and interrupted time series. Two independent reviewers abstracted all data, and disagreements were resolved by consensus and discussion with a third reviewer. The primary outcome was the absolute reduction in the proportion of patients receiving antibiotics.Forty-three studies reporting 55 separate trials met inclusion criteria. Most studies (N = 38) addressed prescribing for acute respiratory infections (ARIs). Among the 30 trials eligible for quantitative analysis, the median reduction in the proportion of subjects receiving antibiotics was 9.7% [interquartile range (IQR), 6.6–13.7%] over 6 months median follow-up. No single QI strategy or combination of strategies was clearly superior. However, active clinician education strategies trended toward greater effectiveness than passive strategies (P = 0.096). Compared with studies targeting specific conditions or patient populations, broad-based interventions extrapolated to larger community-level impacts on total antibiotic use, with savings of 17–117 prescriptions per 1000 person-years. Study methodologic quality was fair.QI efforts are effective at reducing antibiotic use in ambulatory settings, although much room for improvement remains. Strategies using active clinician education and targeting management of all ARIs (rather than single conditions in single age groups) may yield larger reductions in community-level antibiotic use.