PURPOSE: The use of antibiotic prophylaxis in trauma patients, particularly to prevent ventilator-associated pneumonia (VAP), is debated due to rising antibiotic resistance. Therefore, this systematic review evaluated the safety and effectiveness of antibiotic prophylaxis compared to placebo or standard care on clinical outcomes in adult polytrauma patients. METHODS: We searched PubMed and the Cochrane Central Register of Controlled Trials to identify completed and ongoing studies from database inception to April 20, 2023. Eligible studies included systematic reviews and randomized controlled trials (RCTs) comparing antibiotic prophylaxis to placebo or standard care in adult polytrauma patients admitted to the intensive care unit (ICU). RESULTS: Of 1237 identified records, three RCTs involving 256 patients (n CONCLUSION: The results indicate that antibiotic prophylaxis has no significant effect on mortality and clinical status compared with placebo or standard care in adult polytrauma patients but may reduce the risk of VAP. However, the evidence is outdated and of very low certainty, with insufficient data to draw definitive conclusions regarding efficacy. Therefore, high-quality, up-to-date research is urgently needed to support clinical decision-making, and current interpretations should be treated with caution.