OBJECTIVES: Despite strong evidence supporting proning in acute respiratory distress syndrome, few eligible patients receive it. This study determines the cost-effectiveness of interventions to increase utilization of proning for severe acute respiratory distress syndrome. DESIGN: We created decision trees to model severe acute respiratory distress syndrome from ICU admission through death (societal perspective) and hospital discharge (hospital perspective). We assumed patients received low tidal volume ventilation. We used short-term outcome estimates from the PROSEVA trial and longitudinal cost and benefit data from cohort studies. In probabilistic sensitivity analyses, we used distributions for each input that included the fifth to 95th percentile of its CI. SETTING: ICUs that care for patients with acute respiratory distress syndrome. SUBJECTS: Patients with moderate to severe acute respiratory distress syndrome. INTERVENTIONS: The implementation of a hypothetical intervention to increase the appropriate utilization of prone positioning. MEASUREMENTS AND MAIN RESULTS: In the societal perspective model, an intervention that increased proning utilization from 16% to 65% yielded an additional 0.779 (95% CI, 0.088-1.714) quality-adjusted life years at an additional long-term cost of $31,156 (95% CI, -$158 to $92,179) (incremental cost-effectiveness ratio = $38,648 per quality-adjusted life year [95% CI, $1,695-$98,522]). If society was willing to pay $100,000 per quality-adjusted life year, any intervention costing less than $51,328 per patient with moderate to severe acute respiratory distress syndrome would represent good value. From a hospital perspective, the intervention yielded 0.072 (95% CI, 0.008-0.147) more survivals-to-discharge at a cost of $5,242 (95% CI, -$19,035 to $41,019) (incremental cost-effectiveness ratio = $44,615 per extra survival [95% CI, -$250,912 to $558,222]). If hospitals were willing to pay $100,000 per survival-to-discharge, any intervention costing less than $5,140 per patient would represent good value. CONCLUSIONS: Interventions that increase utilization of proning would be cost-effective from both societal and hospital perspectives under many plausible cost and benefit assumptions.