INTRODUCTION: The pathophysiology of the inflammatory response after major trauma is complex and the magnitude correlates with severity of tissue injury and outcomes. Study of infection-mediated immune pathways have demonstrated that cellular microRNAs may modulate the inflammatory response. The authors hypothesize that the expression of microRNAs would correlate to Complicated Recoveries in polytrauma patients (PtPs). METHODS: PtPs enrolled in the prospective observational Tissue and Data Acquisition Protocol with Injury Severity Score (ISS) >15 were selected for this study. PtPs were divided into Complicated Recoveries and uncomplicated recovery groups. PtPs blood samples were obtained at the time of admission (T0). Established biomarkers of systemic inflammation, including cytokines and chemokines were measured using multiplexed Luminex-based methods and novel microRNAs were measured in plasma samples using multiplex RNA hybridization. RESULTS: PtPs (n = 180) had high ISS (26 [20-34]) and Complicated Recovery rate of 33%. microRNAs were lower in PtPs at T0 compared to healthy controls, and bivariate analysis demonstrated that variations of microRNAs correlated with age, race, comorbidities, venous thromboembolism, pulmonary complications, Complicated Recovery, and mortality. Positive correlations were noted between microRNAs and IL-10, VEGF, APACHE, and SOFA scores. Multivariable LASSO analysis of predictors of Complicated Recovery based on microRNAs, cytokines and chemokines, revealed that miR-21-3p and MCP-1 were predictive of Complicated Recovery with an AUC of 0.78. CONCLUSION: Systemic microRNAs were associated with poor outcomes in PtPs, and results are consistent with previously described trends in critically ill patients. These early biomarkers of inflammation might provide predictive utility in early Complicated Recovery diagnosis and prognosis. Due to their potential to regulate immune responses microRNAs may provide therapeutic targets for immunomodulation. LEVEL OF EVIDENCE: II, Diagnostic Tests