This study aimed to determine the clinical course of patients and the quality of antibiotic use using a systematic and unsolicited post-prescription antibiotic review. Seven hundred and fifty-three adult patients receiving antibiotic therapy for 3-5 days were randomized to receive either a post-prescription review by the infectious disease physician (IDP), followed by a recommendation to the attending physician to modify the prescription when appropriate, or no systematic review of the prescription. In the intervention group, 63.3% of prescriptions prompted IDP recommendations, which were mostly followed by ward physicians (90.3%). Early antibiotic modifications were more frequent in the intervention group (57.1% vs. 25.7%, p <0.0001), including stopping therapy, shortening duration and de-escalating broad-spectrum antibiotics. IDP intervention led to a significant reduction of the median [IQR] duration of antibiotic therapy (6 [4-9] vs. 7 days [5-9], p <0.0001). In-hospital mortality, ICU admission and new course of antibiotic therapy rates did not differ between the two groups. Fewer patients in the intervention group were readmitted for relapsing infection (3.4% vs. 7.9%, p 0.01). There was a trend for a shorter length of hospital stay in patients suffering from community-acquired infections in the intervention group (5 days [3-10] vs. 6 days [3-14], p 0.06). This study provides clinical evidence that a post-prescription antibiotic review followed by unsolicited IDP advice is effective in reducing antibiotic exposure of patients and increasing the quality of antibiotic use, and may reduce hospital stay and relapsing infection rates, with no adverse effects on other patient outcomes.