Nosocomial pneumonias, usually due to gram-negative bacilli, occurred in 13 consecutive baboons that underwent endotracheal intubation, prolonged deep sedation, and paralysis during studies of acute respiratory failure. Serial bacteriologic studies demonstrated colonization of the oropharynx by pathogenic bacteria within 24 to 48 h of instrumentation, followed by aspiration of colonizing organisms into the tracheobronchial tree. Specimens obtained from the lung periphery remained sterile for at least 24 h longer than the proximal airways. Despite the presence of multiple pathogenic species in oropharyngeal and tracheobronchial secretions, pneumonias were usually due to a single species selected from those colonizing more proximal regions. In an attempt to prevent pneumonias, we added 3 measures to the management of the next 19 animals: meticulous aspiration of oropharyngeal secretions, topical instillation of polymyxin B, and prophylactic administration of ampicillin beginning 3 days prior to study. These measures reduced the prevalence of colonization with Pseudomonas aeruginosa, Klebsiella pneumoniae, and Staphylococcus aureus, and only 3 of the 19 animals developed pneumonia. This dramatic reduction of pneumonias is explained in part by prevention of colonization by highly invasive organisms. These data indicate that manipulation of the bacterial flora of the upper respiratory tract may provide an effective approach to the prevention of nosocomial pneumonias.