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To determine the effect of a 2-yr multifaceted program aimed at preventing ventilator-acquired pneumonia on compliance with eight targeted preventive measures.Pre- and postintervention observational study.A 20-bed medical intensive care unit in a teaching hospital.A total of 1649 ventilator-days were observed.The program involved all healthcare workers and included a multidisciplinary task force, an educational session, direct observations with performance feedback, technical improvements, and reminders. It focused on eight targeted measures based on well-recognized published guidelines, easily and precisely defined acts, and directly concerned healthcare workers' bedside behavior. Compliance assessment consisted of five 4-wk periods (before the intervention and 1 month, 6 months, 12 months, and 24 months thereafter).Hand-hygiene and glove-and-gown use compliances were initially high (68% and 80%) and remained stable over time. Compliance with all other preventive measures was initially low and increased steadily over time (before 2-yr level, p < .0001): backrest elevation (5% to 58%) and tracheal cuff pressure maintenance (40% to 89%), which improved after simple technical equipment implementation; orogastric tube use (52% to 96%); gastric overdistension avoidance (20% to 68%); good oral hygiene (47% to 90%); and nonessential tracheal suction elimination (41% to 92%). To assess overall performance of the last six preventive measures, using ventilator-days as the unit of analysis, a composite score for preventive measures applied (range, 0–6) was developed. The median (interquartile range) composite scores for the five successive assessments were 2 (1–3), 4 (3–5), 4 (4–5), 5 (4–6), and 5 (4–6) points; they increased significantly over time (p < .0001). Ventilator-acquired pneumonia prevalence rate decreased by 51% after intervention (p < .0001).Our active, long-lasting program for preventing ventilator-acquired pneumonia successfully increased compliance with preventive measures directly dependent on healthcare workers' bedside performance. The multidimensional framework was critical for this marked, progressive, and sustained change.