Objective To explore the relationship between peripheral blood high mobility protein-1 (HMGB-1), procalcitonin (PCT) levels and injury severity score (ISS) in patients with severe multiple trauma, and evaluate multiple organ dysfunction syndrome (MODS).Methods 109 patients with severe multiple trauma who were treated in our hospital from January 2019 to October 2023, including 62 patients with MODS and 47 patients without MODS. The differences in blood HMGB-1, PCT levels and ISS scores between patients with and without MODS were analyzed, as well as the differences in prognosis among patients with MODS. The value of predicting the prognosis of patients with MODS by HMGB-1, PCT levels were analyzed. Results The HMGB-1, PCT, and ISS scores of patients with MODS were (2.94 ± 0.88) mg/L, (6.75 ± 1.02) mg/L, and (22.24 ± 2.32) points, respectively, which were significantly higher than those of patients without MODS (P＜0.05). The HMGB-1, PCT, and ISS scores of patients with MODS death were (3.21 ± 0.92) mg/L, (7.15 ± 0.99) mg/L, and (22.98 ± 1.97) points, respectively, which were significantly higher than those of surviving MODS patients (P＜0.05). HMGB-1, PCT, and ISS scores were positively correlated (r=0.723 and 0.795, P＜0.05). The area under the ROC curve for predicting mortality in patients with MODS using HMGB-1 and PCT were 0.781 (95%CI: 0.655~0.907) and 0.818 (95% CI: 0.708~0.928), respectively (P＜0.05), cut-off values was 2.96mg/L and 6.37mg/L, sensitivity was 75.00% and 85.00%, specificity was 86.40% and 68.20%, respectively.Conclusion The levels of HMGB-1 and PCT in peripheral blood of patients with severe multiple trauma, are positively correlated with ISS score. Patients with MODS have significantly increased levels of HMGB-1 and PCT, which has certain application value in predicting the prognosis of patients with MODS