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The aim of this study is to assess the associations between the timing of secondary definitive fracture surgery on inflammatory changes and outcome in the patient with multiple injuries. The study population consists of a series of patients with multiple injuries who were managed using a strategy of primary temporary skeletal stabilization followed by delayed definitive fracture fixation.In a prospective cohort study performed at a Level I trauma center, the patients’ injuries and operative details as well as immune markers and clinical outcomes were studied. The patients were split into an early secondary surgery group (group ESS, surgery at days 2–4) and a late secondary surgery group (group LSS, surgery at days 5–8). During the posttraumatic course, inflammatory markers (interleukin [IL]-6, tumor necrosis factor-α) were determined on a daily basis. Perioperatively, these markers were additionally evaluated at 30 minutes, 7 hours, and 24 hours after initiation of surgery.Secondary surgery on days 2 to 4 was associated with a higher incidence of postoperative organ dysfunction (n = 33 [46.5%]) than secondary surgery on days 5 to 8 (n = 9 [15.7%], p = 0.01). A significant association between the combination of initial IL-6 values > 500 pg/dL plus surgery on days 2 to 4 and the development of multiple organ failure (r = 0.96, p < 0.001) occurred. A correlation between the initial IL-6 values > 500 pg/dL and surgery on days 5 to 8 (r = 0.57, p < 0.07) could not be found. IL-6 also demonstrated a predictive value for the development of multiple organ failure: IL-6 > 500 pg/dL in group ESS, r = 0.96, p < 0.001; IL-6 > 500 pg/dL in group LSS, r = 0.57, p < 0.07.According to our data, no distinct clinical advantage in carrying out secondary definitive fracture fixation early could be determined. In contrast, in patients who demonstrated initial IL-6 values above 500 pg/dL, it may be advantageous to delay the interval between primary temporary fracture stabilization and secondary definitive fracture fixation for more than 4 days. In patients with blunt multiple injuries undergoing primary temporary fixation of major fractures, the timing of secondary definitive surgery should be carefully selected, because it may act as a second hit phenomenon and cause a deterioration of the clinical status.