A novel regimen of selective decontamination (SDD) with initial systemic cefotaxime prevented bacterial colonization of the oropharynx and stomach in mechanically ventilated patients. In a three-group study of all patients receiving prolonged mechanical ventilation, patients in control groups A and B received antibiotics only when infection was present. In group A, antibiotics that disturb colonization resistance (CR) were used. In group B, antibiotics use was restricted to antibiotics not affecting CR. Patients in group C received SDD, consisting of norfloxacin, polymyxin E and amphotericin B, administered via a gastric tube and applied to the oropharynx. Group C patients further received an initial five day course of cefotaxime, 500 mg tid. The lower respiratory tract was colonized with microorganisms on admission in about half of the patients, and this persisted in both control groups. In group C, lower respiratory tract colonization was eliminated in all patients after five days. In both control groups about 90% of the patients acquired microbial colonization of the oropharynx and stomach, mostly with Gram-negative bacilli. In group C, only 12% and 24% of the patients acquired colonization of the oropharynx and stomach respectively (P less than 0.001). The oropharynx and stomach were the major sources of microorganisms causing lower respiratory tract infection in both control groups. In group C, elimination of oropharyngeal and gastric colonization completely prevented lower respiratory tract infection from these sources.