Abstract: Antibiotic resistance is increasing worldwide. The implementation of  antibiotic stewardship programmes (ASPs) is of utmost importance to  optimize antibiotic use in order to prevent resistance development  without harming patients. The emergency department (ED), cornerstone  between hospital and community, represents a crucial setting for  addressing ASP implementation; however, evidence data on ASP in ED are  poor. In this study, a 4-year, non-restrictive, multi-faceted ASP was  implemented in a general ED with the aim to evaluate its impact on  antibiotic use and costs. Secondly, the study focused on assessing the  impact on length of hospital stay (LOS), Clostridioides difficile  infection (CDI) incidence rate, and mortality in the patients' group  admitted from ED to medical wards. The ASP implementation was associated  with a reduction of antibiotic use and costs. A mild but sustained LOS  decrease in all medical wards and a significant downward trend of CDI  incidence rate were observed, while mortality did not significantly  change. In conclusion, the implementation of our ED-based ASP has  demonstrated to be feasible and safe and might clinically benefit the  hospital admitted patients' group. Further research is needed to  identify the most suitable ASP design for ED and the key outcome  measures to reliably assess its effectiveness.