Background: Acute respiratory infections (ARIs) are a key target to improve antibiotic use in the outpatient setting. The Core Elements of Outpatient Antibiotic Stewardship provide a framework for improving antibiotic use, but data on safety and effectiveness of interventions to improve antibiotic use are limited. We report the impact of Core Elements implementation within Veterans’ Healthcare Administration clinics on antibiotic prescribing and patient outcomes. Methods: The intervention targeting treatment of uncomplicated ARIs (sinusitis, pharyngitis, bronchitis, and viral upper respiratory infections [URIs]) in emergency department and primary care settings was initiated within 10 sites between September 2017 and January 2018. The intervention was developed using the Core Elements and included local site champions, audit-and-feedback with peer comparison, and academic detailing. We evaluated the following outcomes: per-visit antibiotic prescribing rates overall and by diagnosis; appropriateness of treatment; 30-day ARI revisits; 30-day infectious complications (eg,, pneumonia,); 30-day adverse medication effects; 90-day Clostridium difficile infection (CDI); and 30-day hospitalizations. Multilevel logistic regression was used to calculate rate ratios (RR) with 95% CI for each outcome in the postintervention period (12 months) compared to the preintervention period (39–42 months). Results: There were 14,020 uncomplicated ARI visits before the intervention and 4,866 uncomplicated ARI visits after the intervention. The proportions of uncomplicated ARI visits with antibiotics prescribed were 59.17% before the intervention versus 44.34% after the intervention. A trend in reduced antibiotic prescribing for ARIs throughout the entire (before and after) observation period was evident (0.92; 95% CI, 0.90–0.94); however, a significant reduction in antibiotic prescribing after the intervention was identified (0.74; 95% CI, 0.59–0.93). Per-visit antibiotic prescribing rates decreased significantly for bronchitis and URI (0.54; 95% CI, 0.44–0.65), pharyngitis (0.76; 95% CI, 0.67–0.86), and sinusitis (0.92; 95% CI, 0.85–1.0). Appropriate therapy for pharyngitis increased (1.43; 95% CI, 1.21–1.68), but appropriate therapy for sinusitis remained unchanged (0.92; 95% CI, 0.85–1.0) after the intervention. Complications associated with antibiotic undertreatment were not different after the intervention: ARI-related revisit rates (1.01; 95% CI, 0.98–1.05) and infectious complications (1.01; 95% CI, 0.79–1.28). A potential benefit of improved antibiotic use included a reduction in visits for adverse medication effects (0.82; 95% CI, 0.72–0.94). Furthermore, 90-day CDI events were too sparse to model: preintervention incidence was 0.08% and postintervention incidence was 0.06%. Additionally, 30-day hospitalizations were significantly lower in the postintervention period (0.79; 95% CI, 0.72–0.87). Conclusions: Implementation of the Core Elements was safe and effective and was associated with reduced antibiotic prescribing rates for uncomplicated ARIs, improvements in diagnosis-specific appropriate therapy, visits for adverse antibiotic effects, and 30-day hospitalization rates. No adverse events were noted in ARI-related revisit rates or infectious complications. CDI rates were low and unchanged.