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The “Pneumonia Zero” project is a nationwide multimodal intervention based on the simultaneous implementation of a comprehensive evidence-based bundle measures to prevent ventilator-associated pneumonia in critically ill patients admitted to the ICU.Prospective, interventional, and multicenter study.A total of 181 ICUs throughout Spain.All patients admitted for more than 24 hours to the participating ICUs between April 1, 2011, and December 31, 2012.Ten ventilator-associated pneumonia prevention measures were implemented (seven were mandatory and three highly recommended). The database of the National ICU-Acquired Infections Surveillance Study (Estudio Nacional de Vigilancia de Infecciones Nosocomiales [ENVIN]) was used for data collection. Ventilator-associated pneumonia rate was expressed as incidence density per 1,000 ventilator days. Ventilator-associated pneumonia rates from the incorporation of the ICUs to the project, every 3 months, were compared with data of the ENVIN registry (April–June 2010) as the baseline period. Ventilator-associated pneumonia rates were adjusted by characteristics of the hospital, including size, type (public or private), and teaching (postgraduate) or university-affiliated (undergraduate) status.The 181 participating ICUs accounted for 75% of all ICUs in Spain. In a total of 171,237 ICU admissions, an artificial airway was present on 505,802 days (50.0% of days of stay in the ICU). A total of 3,474 ventilator-associated pneumonia episodes were diagnosed in 3,186 patients. The adjusted ventilator-associated pneumonia incidence density rate decreased from 9.83 (95% CI, 8.42–11.48) per 1,000 ventilator days in the baseline period to 4.34 (95% CI, 3.22–5.84) after 19–21 months of participation.Implementation of the bundle measures included in the “Pneumonia Zero” project resulted in a significant reduction of more than 50% of the incidence of ventilator-associated pneumonia in Spanish ICUs. This reduction was sustained 21 months after implementation.