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Ventilator-associated events are associated with increased mortality, prolonged mechanical ventilation, and longer ICU stay. Given strong national interest in improving ventilated patient care, the National Institute of Health and Agency for Healthcare Research and Quality funded a two-state collaborative to reduce ventilator-associated events. We describe the collaborative’s impact on ventilator-associated event rates in 56 ICUs.Longitudinal quasi-experimental study.Fifty-six ICUs at 38 hospitals in Maryland and Pennsylvania from October 2012 to March 2015.We organized a multifaceted intervention to improve adherence with evidence-based practices, unit teamwork, and safety culture. Evidence-based interventions promoted by the collaborative included head-of-bed elevation, use of subglottic secretion drainage endotracheal tubes, oral care, chlorhexidine mouth care, and daily spontaneous awakening and breathing trials. Each unit established a multidisciplinary quality improvement team. We coached teams to establish comprehensive unit-based safety programs through monthly teleconferences. Data were collected on rounds using a common tool and entered into a Web-based portal.ICUs reported 69,417 ventilated patient-days of intervention compliance observations and 1,022 unit-months of ventilator-associated event data. Compliance with all evidence-based interventions improved over the course of the collaborative. The quarterly mean ventilator-associated event rate significantly decreased from 7.34 to 4.58 cases per 1,000 ventilator-days after 24 months of implementation (p = 0.007). During the same time period, infection-related ventilator-associated complication and possible and probable ventilator-associated pneumonia rates decreased from 3.15 to 1.56 and 1.41 to 0.31 cases per 1,000 ventilator-days (p = 0.018, p = 0.012), respectively.A multifaceted intervention was associated with improved compliance with evidence-based interventions and decreases in ventilator-associated event, infection-related ventilator-associated complication, and probable ventilator-associated pneumonia. Our study is the largest to date affirming that best practices can prevent ventilator-associated events.