We evaluated the effect of selective decontamination of the digestive tract (SDD) on the incidence of ventilator-associated pneumonia (VAP) and its associated morbidity and cost in a mixed population of intubated patients. Two hundred seventy-one consecutive patients admitted to the intensive care units (ICUs) of five teaching hospitals and who had an expected need for intubation exceeding 48 h were enrolled and received topical antibiotics or placebo. Uninfected patients additionally received ceftriaxone or placebo for 3 d. VAP occurred in 11.4% of SDD-treated and 29.3% of control-group patients (p < 0.001; 95% confidence interval [CI]: 7.8 to 27.9). The incidence of nonrespiratory infections in the two groups was 19.1% and 30.7%, respectively (p = 0.04; 95% CI: 0.7 to 22.7). Among survivors, the median length of ICU stay was 11 d (interquartile range: 7 to 21.5 d) for the SDD-treated group and 16. 5 d (10 to 30 d) for the control group (p = 0.006). Mean cost per survivor was $11,926 for treated and $16,296 for control-group patients. Mortality was 38.9% and 47.1%, respectively (p = 0.57). In decontaminated patients, the prevalence of gram-negative bacilli fell within 7 d from 47.4% to 13.0% (p < 0.001), whereas colonization with resistant gram-positive strains was higher (p < 0. 05) than in the placebo group. In a mixed population of intubated patients, SDD was associated with a significant reduction of morbidity at a reduced cost. Our findings support the use of SDD in this high-risk group.