We prospectively studied the impact of an antibiotic prophylaxis regimen on the incidence of infections, organ dysfunctions, and mortality in a predominantly surgical and trauma intensive care unit (ICU) population. A total of 546 patients were enrolled and stratified according to Acute Physiology and Chronic Health Evaluation (APACHE)-II scores. They were then randomized to receive either 2 400 mg of intravenous ciprofloxacin for 4 days, together with a mixture of topical gentamicin and polymyxin applied to the nostrils, mouth, and stomach throughout their ICU stay or to receive intravenous and topical placebo. When receiving prophylaxis, significantly fewer patients acquired infections (p 0.001, risk ratio [RR], 0.477; 95% confidence interval [CI], 0.367–0.620), especially pneumonias (6 versus 29, p 0.007), other lower respiratory tract infections (39 versus 70, p 0.007), bloodstream infections (14 versus 36, p 0.007), or urinary tract infections (36 versus 60, p 0.042). Also, significantly fewer patients acquired severe organ dysfunctions (63 versus 96 patients, p 0.0051; RR, 0.636; 95% CI, 0.463–0.874), especially renal dysfunctions (17 versus 38; p 0.018). Within 5 days after admission, 24 patients died in each group, whereas 28 patients receiving prophylaxis and 51 receiving placebo died in the ICU thereafter (p 0.0589; RR, 0.640; 95% CI, 0.402–1.017). The overall ICU mortality was not statistically different (52 versus 75 fatalities), but the mortality was significantly reduced for 237 patients of the midrange stratum with APACHE-II scores of 20–29 on admission (20 versus 38 fatalities, p 0.0147; RR, 0.508; 95% CI, 0.295–0.875); there was still a favorable trend after 1 year (51 versus 60 fatalities; p 0.0844; RR, 0.720; 95% CI, 0.496–1.046). Surveillance cultures from tracheobronchial, oropharyngeal, and gastric secretions and from rectal swabs did not show any evidence for the selection of resistant microorganisms in the patients receiving prophylaxis.