Patients requiring long-term ventilation are at high risk of lower airway infections, generally of endogenous development. Patients on long-term ventilation, in particular via a tracheostomy, may develop tracheobronchitis or pneumonia of exogenous pathogenesis, ie, caused by microorganisms not carried in the oropharynx. The frequency of exogenous colonization or infection has previously been reported to be as high as 33%. A prospective observational cohort study of 2 years was undertaken to evaluate the efficacy of topical antibiotics in the prevention of exogenous colonization or infection of the lower airways. The antibiotic combination of polymyxin E and tobramycin in a 2% paste was applied four times a day on the tracheostoma. A total of 23 children (median age, 4.1 months; range, 0 to 215 months) were enrolled in the study from September 1, 1996, until August 30, 1998. Surveillance samples of the oropharynx were obtained before tracheostomy and thereafter twice weekly. Diagnostic samples of the lower airways were taken once weekly and on clinical indication. Fourteen children (61%) had a total of 16 episodes of tracheal colonization or infection with 20 potentially pathogenic microorganisms. Only one child had tracheobronchitis with Streptococcus pneumoniae and Haemophilus influenzae during the 2-year study. Of the 16 colonization episodes, 12 (75%) were of primary endogenous pathogenesis, ie, caused by microorganisms present in the oropharynx at the time of tracheostomy. Community microorganisms including S pneumoniae, H influenzae, Moraxella (Branhamella) catarrhalis, and Staphylococcus aureus were the predominating bacteria. Three patients acquired nosocomial bacteria Pseudomonas aeruginosa and Hafnia alvei in the oropharynx, subsequently followed by secondary colonization of the lower airways. There was one failure of the prophylaxis: one patient (4%) had exogenous colonization with Pseudomonas pickettii. Topical antibiotics applied to the tracheostoma were found to be effective in reducing the exogenous route of colonization of the lower respiratory tract, compared with clinical experience and the literature. This promising technique requires further evaluation in randomized trials.