Objective: To define the influence of prior antibiotic use on the etiology and mortality of ventilator-associated pneumonia (VAP). Setting: A university hospital medical-surgical ICU. Design: Prospective clinical study. Methods: Over a 35-month period, we prospectively studied 129 consecutive episodes of VAP. Etiologic diagnosis was established using a protected specimen brush and quantitative culture techniques. We examined prognostic factors by univariate and multivariate analyses using a statistical software package (SPSS). Results: The rate of VAP caused by Gram-positive cocci or Haemophilus influenzae was statistically lower (p<0.05) in the patients who had received antibiotics previously, while the rate of VAP caused by Pseudomonas aeruginosa was statistically higher (p<0.01). Patients died of causes directly related to the infection in 18 (14.0 percent) episodes, P aeruginosa being isolated in 9 of these fatal cases. Indeed, we found that 27.7 percent (15/54) of patients who had received prior antimicrobial therapy before the onset of pneumonia died, compared with only 4.0 percent (3/75) of those who did not. In the univariate analysis, the variables significantly associated with attributable mortality were age older than 45 years, use of corticosteroids, presence of shock, hospital day of VAP over 9, antecedent COPD, and a prior antibiotic use. A step-forward logistic regression analysis defined only prior antibiotic use (p<0.0001, OR=9.2) as significantly influencing the risk of death from VAP. The same result was obtained when severity was included in the model. However, prior antibiotic use entirely dropped out as a significant risk factor when the etiologic agent was included in the regression equation. Conclusions: Distribution of infecting microorganisms responsible for VAP differs in patients who received prior antimicrobial therapy, and this factor determines a higher mortality rate. We suggest a restrictive antibiotic policy in mechanically ventilated patients with the purpose of reducing the risk of death from VAP.