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Objectives: Flail chest is a common injury sustained by patients who experience high-energy blunt chest trauma and results in severe respiratory compromise because of altered mechanics of respiration. There has been increased interest in operative fixation of these injuries with the intention of restoring the mechanical integrity of the chest wall, and several studies have shown that ventilation requirements and pulmonary complications may be decreased with operative intervention. The purpose of this study was to evaluate fixation of rib fractures in flail chest injuries using cost-effectiveness analysis, supported by systematic review and meta-analysis., Methods: This was a 2-part study in which we initially conducted a systematic literature review and meta-analysis on outcomes after operative fixation of flail chest injuries, evaluating intensive care unit (ICU) stay, hospital length of stay (LOS), mortality, pneumonia, and need for tracheostomy. The results were then applied to a decision-analysis model comparing the costs and outcomes of operative fixation versus nonoperative treatment. The validity of the results was tested using probabilistic sensitivity analysis., Results: Operative treatment decreased mortality, pneumonia, and tracheotomy (risk ratios of 0.44, 0.59, and 0.52, respectively), as well as time in ICU and total LOS (3.3 and 4.8 days, respectively). Operative fixation was associated with higher costs than nonoperative treatment ($23,682 vs. $8629 per case, respectively) and superior outcomes (32.60 quality-adjusted life year (QALY) vs. 30.84 QALY), giving it an incremental cost-effectiveness ratio of $8577/QALY., Conclusions: Surgical fixation of rib fractures sustained from flail chest injuries decreased ICU time, mortality, pulmonary complications, and hospital LOS and resulted in improved health care-related outcomes and was a cost-effective intervention. These results were sensitive to overall complication rates, and operations should be conducted by surgeons or combined surgical teams comfortable with both thoracic anatomy and exposures as well as with the principles and techniques of internal fixation., Level of Evidence: Economic Level III. See Instructions for Authors for a complete description of levels of evidence.