BACKGROUND: Ventilator-associated pneumonia (VAP), the most common hospital-acquired infection in intensive care units, increases mortality and health care costs. We describe the long-term impact of a multifaceted program for decreasing VAP rates that markedly improved compliance with 8 targeted preventive measures. METHODS: We compared VAP rates during a 45-month baseline period and a 30-month intervention period in a cohort of patients who received mechanical ventilation for > 48 h. VAP was diagnosed on the basis of quantitative cultures of distal specimens. VAP incidence density rates were expressed as total VAP episodes over total mechanical ventilation duration and as first VAP episodes over mechanical ventilation duration at VAP or hospital discharge. We used segmented regression analysis and a Cox proportional hazard model to assess the impact of the program on first VAP occurrence. RESULTS: Baseline and intervention VAP rates were 22.6 and 13.1 total VAP episodes over total mechanical ventilation duration per 1000 ventilation-days, respectively, and 26.1 and 14.9 first VAP episodes over mechanical ventilation duration at VAP or hospital discharge per 1000 procedure-days, respectively (P < .001). VAP rates decreased by 43% in both statistical analyses and remained significant after adjustment for confounders (Cox adjusted hazard ratio, 0.58; 95% confidence interval, 0.46-0.72; P < .001). Daily VAP hazard rates on ventilation days 5, 10, and 15 were 2.6%, 3.5%, and 3.4%, respectively, during the baseline period and 1.4%, 2.3%, and 2%, respectively, during the intervention period. CONCLUSION: Our preventive program produced sustained VAP rate decreases in the long term. However, VAP rates remained substantial despite high compliance with preventive measures, suggesting that eliminating VAP in the intensive care unit may be an unrealistic goal.