Background: Antibiotic stewardship (AS) is a cornerstone of the fight  against antimicrobial resistance. However, evidence on the best practice  to improve antibiotic prescription in various hospital settings is  still scarce. Aim of this study was to measure the efficacy of a  non-restrictive AS intervention in the internal medicine area of a  tertiary-care hospital across a three-year period.  Methods: The  intervention was composed of a three-month 'intensive phase' based on  education and guidelines provision, followed by nine-month of  audits-and-feedbacks activities. The primary outcome was the overall  antibiotic consumption measured as Days-Of-Therapy (DOTs),  Defined-Daily-Doses (DDDs). Secondary outcomes were carbapenems and  fluoroquinolones consumption, all-cause in-hospital mortality,  length-of-stay, incidence of Clostridioides difficile (CDIs) and  carbapenem-resistant Enterobacterales bloodstream infections (CRE-BSIs).  All outcomes were measured in the intervention wards comparing the pre-  with the post- phase using an interrupted-time-series model.  Results: A  total of 145337 patient-days and 14159 admissions were included in the  analysis. The intervention was associated with reduced DOTs*1000PDs  (-162.2/P=0.005) and DDDs*1000PDs (-183.6/P=<0.001). A sustained  decrease in ward-related antibiotic consumption was detected also during  the post-intervention phase and in the carbapenems/fluoroquinolones  classes. The intervention was associated with an immediate reduction in  length-of-stay (-1.72 days/P<0.001) and all-cause mortality (-3.71  deaths*100 admissions/P=0.002) with a decreasing trend over time. Rates  of CDIs and CRE-BSIs were not significantly impacted by the  intervention.  Conclusions: The AS intervention was effective and safe  in decreasing antibiotic consumption and LOS in the internal medicine  area. Enabling prescribers to judicious use of antimicrobials through  active participation in AS initiatives is key to reach sustained results  over time.