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The economic implications of sedative choice in the management of patients receiving mechanical ventilation are unclear because of differences in costs and clinical outcomes associated with specific sedatives. Therefore, we aimed to determine the cost-effectiveness of the most commonly used sedatives prescribed for mechanically ventilated critically ill patients.Adopting the perspective of a hospital, we developed a probabilistic decision model to determine whether continuous propofol or intermittent lorazepam was associated with greater value when combined with daily awakenings. We also evaluated the comparative value of continuous midazolam in secondary analyses. We assumed that patients were managed in a medical intensive care unit and expected to require ventilation for ≥48 hrs. Model inputs were derived from primary analysis of randomized controlled trial data, medical literature, Medicare reimbursement rates, pharmacy databases, and institutional data.We measured cost-effectiveness as costs per mechanical ventilator–free day within the first 28 days after intubation. Our base-case probabilistic analysis demonstrated that propofol dominated lorazepam in 91% of simulations and, on average, was both $6,378 less costly per patient and associated with more than three additional mechanical ventilator–free days. The model did not reveal clinically meaningful differences between propofol and midazolam on costs or measures of effectiveness.Propofol has superior value compared with lorazepam when used for sedation among the critically ill who require mechanical ventilation when used in the setting of daily sedative interruption.