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Purpose: Postinjury multiple organ failure (MOF) is the sequela to the disease of polytrauma. We aimed to describe the contemporary population-based epidemiology of MOF within a mature trauma system, to analyse the time taken for MOF to develop, and to evaluate the temporal patterns and contributions of the individual constituent organ failures. Methods: Prospective observational study conducted across five Level-1 trauma centers in New South Wales, Australia. Trauma patients at-risk of MOF (Denver > 3 from 48 h post-admission), aged > 16 years, ISS > 15, and who stayed in ICU for ≥ 48 h were eligible for inclusion. Results: From May 2018–February 2021, 600 at-risk polytrauma patients were prospectively enrolled (mean(SD)age = 49(21)years, males = 453/600(76%),median(IQR)ISS = 26(20,34)). MOF incidence was 136/600(23%) among at-risk patients, 142/6248(2%) among major trauma patients (ISS > 12 per Australian definition), and 0.8/100,000 in the general population. The mortality rate was 55/600(11%) in the overall study population, and 34/136(25%) in MOF patients. 82/136(60%) of MOF patients developed MOF on day-3. No patients developed MOF after day-13. Among MOF patients, 60/136(44%) had cardiac failures (mortality = 37%), 39/136(29%) had respiratory failures (mortality = 23%), 24/136(18%) had renal failures (mortality = 63%), and 12/136(9%) had hepatic failures (mortality = 50%). Conclusion: Although a rare syndrome in the general population, MOF occurred in 23% of the most severely injured polytrauma patients. When compared to previous risk-matched cohorts, MOF become more common, but not more lethal, despite a decade older cohort. The heart has superseded the lungs as the most common organ to fail. Cardiac and respiratory failures occurred earlier and were associated with lower mortality than renal and hepatic failures. [ABSTRACT FROM AUTHOR]