Study objective: To determine whether the development of late-onset ventilator-associated pneumonia (VAP) is associated with an increased risk of hospital mortality. Design: Prospective cohort study. Setting: ICUs of two university-affiliated teaching hospitals. Patients: Three hundred foul-teen patients admitted to an ICU who required mechanical ventilation for greater than 5 days. Interventions: Prospective patient surveillance and data collection. Measurements: The primary outcome measures were the development of late-onset VAP (ie, occurring >96 h after intubation) and hospital mortality. Results: Late-onset VAP was observed in 87 patients (27.7%). Thirty-four (39.1%) patients with late-onset VAP died during hospitalization compared with 85 patients (37.4%) without late-onset VAP (relative risk, 1.04; 95% confidence interval [CI], 0.76 to 1.43). Twenty patients (6.4%) developed late-onset VAP due to a ''high-risk'' pathogen tie, Pseudomonas aeruginosa, Acinetobacter sp, Xanthomonas maltophilia) with an associated mortality rate of 65%. Stepwise logistic regression analysis identified five variables as independent risk factors for hospital mortality (p<0.05): an organ system failure index of 3 or greater (adjusted odds ratio [AOR], 3.4; 95% CI, 2.0 to 5.8; p<0.001), having a nonsurgical diagnosis (AOR, 2.1; 95% CI, 1.3 to 3.6; p=0.002), a premorbid lifestyle score of 2 or greater (AOR, 1.8; 95% CI, 1.1 to 2.9; p=0.015), acquiring late-onset VAP due to a ''high-risk'' pathogen (AOR, 3.4; 95% CI, 1.2 to 10.0; p=0.025), and having received antacids or histamine type-2 receptor antagonists (AOR, 1.7; 95% CI, 1.0 to 2.9; p=0.034), Additionally, we found the occurrence of late-onset. VAP due to high-risk pathogens to be the most important predictor of hospital mortality among patients developing VAP (AOR, 5.4; 95% CI, 2.8 to 10.3; p=0.009). Conclusions: Nosocomial pneumonia due to certain high-risk microorganisms is an independent risk factor for hospital mortality among patients requiring prolonged mechanical ventilation. We suggest that future investigations of late-onset VAP stratify patient outcomes according to the distribution of high-risk pathogens when reporting their results.