Abstract Background Fluoroquinolones are broad spectrum antibiotics with several Food and Drug Administration (FDA)-issued black box warnings. Due to these risks, the FDA recommends reserving fluoroquinolones for situations with no alternatives. Beginning in 2020, the Joint Commission required outpatient antimicrobial stewardship activities due to overprescribing and growing resistance to antimicrobials. The role of this study was to implement a clinical decision support system (CDSS) targeting inappropriate outpatient fluoroquinolone prescribing. Methods This was a single center, quasi-experimental study evaluating patients prescribed oral fluoroquinolones in an outpatient ambulatory care setting between December 1, 2020-February 28, 2021 and December 1, 2021-February 28, 2022. Patients included in this study were divided into Pre-CDSS and Post-CDSS groups if they received oral antibiotics for pre-determined indications (see table 2 for the list of indications). The primary outcome was overall reduction in outpatient fluoroquinolone prescribing. Secondary objectives were reduction in outpatient fluoroquinolone prescribing by indication, orders by provider type, appropriate fluoroquinolone dosing per renal function and incidence of an emergency department (ED) visit or hospitalization within 90 days consistent with a fluoroquinolone adverse drug reaction. Results A total of 2,447 (1,105 in Pre-CDSS vs. 1,342 in Post-CDSS) were included for analysis. Fluoroquinolone prescribing significantly decreased in Post-CDSS group compared to Pre-CDSS group (4.9% vs. 3.4%; p = 0.03). There was a significant reduction in fluoroquinolone prescribing in abscess (8.5% vs. 4.9%; p = 0.003), dental abscess (4.4% vs. 0%; p < 0.00001), sinusitis (2.4% vs. 0.2%; p < 0.00001) and soft skin tissue infections (5.3% vs. 0.8%; p < 0.00001). In the fluoroquinolone subgroups, prescribing per provider type and appropriate dosing per renal function were similar, and there were no adverse events leading to an ED visit or hospitalization within 90 days. Conclusion Implementation of a CDSS resulted in a reduction of overall and targeted indication inappropriate fluoroquinolone prescribing. Disclosures Teri Fanizza, Pharm.D., BCPS, BCIDP, Merck & co inc: Stocks/Bonds|Pfizer Inc: Stocks/Bonds.