The objective of this study was to evaluate the efficacy of antibiotic prophylaxis in association with tube thoracostomy for chest trauma patients with Injury Severity Scores of 9 or 10. A double-blind randomized clinical trial of patients requiring tube thoracostomy was performed at an urban Level 1 trauma center. All patients included in this series were patients with Injury Severity Scores of 9 or 10 (hemothorax/pneumothorax) who suffered isolated chest trauma secondary to blunt or penetrating trauma. Before chest tube placement, 139 patients (34 blunt trauma, 105 penetrating trauma) were blindly randomized to Group A (71 patients) for which they received 1 g cefazolin intravenously every 8 hours or Group B (68 patients) for which they received a placebo intravenously every 8 hours. Antibiotic or placebo was administered before chest tube insertion and continued until the time of chest tube removal. The majority of patients underwent chest tube placement in the emergency room with a small number of delayed pneumothoraces (4 patients) treated after admission. In the 71 patients receiving antibiotic, 7 complications (1 pleural effusion, 2 chest tube reinsertions, 4 additional chest tubes) occurred, none of which were infectious. In the 68 patients receiving placebo, 7 complications (2 empyemas, 2 pneumonias with effusions, 1 pleural effusion, 2 chest tube reinsertions) occurred, 4 of which were infectious and required antibiotic intervention (P = 0.05, Fisher's exact test). This study showed that patients receiving antibiotics have a significantly reduced incidence of infectious complications and suggests that patients who undergo tube thoracostomy for chest trauma would benefit from administration of prophylactic antibiotics.