Secondary pneumonia in patients requiring mechanical ventilation has a high morbidity and mortality. Diagnosis is difficult and treatment failure common; therefore, preventive measures are important. In a double-blind, placebo-controlled trial, we evaluated selective decontamination of the oropharynx with polymyxin B sulfate, neomycin sulfate, and vancomycin hydrochloride (PNV) in 52 patients requiring mechanical ventilation during a 3- to 34-day period (mean, 10 days). Either PNV or placebo was administered six times daily in the oropharynx. During the first 12 days of intubation, tracheobronchial colonization by gramnegative bacteria and Staphylococcus aureus, as well as pneumonia, occurred less frequently in the PNV than in the placebo group (16% vs 78%; P<.0001). Hospital mortality was not different, but systemic antibiotics were prescribed less often in the PNV group and no resistant microorganism emerged. In these critically ill patients, topical oropharyngeal antibiotic application lowered the rate of ventilator-associated pneumonia by a factor of 5, probably by interrupting the stomach-to-trachea route of infection, and decreased the requirement for intravenous antibiotics.