Objective: To evaluate the posttraumatic course of several inflammatory mediators or markers (complement components C3, C3a, terminal complement complex, thromboxane B-2, C-reactive protein, elastase, and neopterin) in relation to the development of multiple organ failure and mortality. Design: Prospective study of a selected patient group. Setting: Surgical intensive care units in three European trauma hospitals. Patients: Patients (n = 56) with severe blunt trauma (Injury Severity Score of greater than or equal to 33). Interventions: Arterial blood samples were sequentially obtained. Measurements and Main Results: Nonsurvivors (n = 8) had significantly higher circulating C3a and elastase concentrations on the first postinjury day, compared with survivors (n = 48). No differences between these groups were found for terminal complement complex, thromboxane B-2, C-reactive protein, and the neopterin/creatinine ratio. Five patients died before day 5. Eighteen patients developed multiple organ failure, which was diagnosed from day 5 onward, leaving 33 patients without multiple organ failure. The patients with subsequent multiple organ failure showed significantly higher mean circulating concentrations of C3a (914 +/- 190 [SEM] ng/mL), terminal complement complex (57 +/- 17 U/ mL), and thromboxane B-2 (275 +/- 37 pg/mL) at the first postinjury day than the patients without multiple organ failure (566 +/- 110 ng/mL, 27 +/- 2 U/mL, and 169 +/- 14 pg/mL, respectively). In patients with multiple organ failure, elastase concentrations were significantly higher on days 2, 3, 4, and 5 postinjury. Neopterin/creatinine ratios, on the other hand, were significantly higher in patients with multiple organ failure when the multiple organ failure had already become established (on days 8 and 10). Conclusion: In multiple trauma patients, excessive triggering of the inflammatory cascade-as expressed by complement activation and stimulation of neutrophils producing elastase-plays an important and early role in the development of multiple organ failure.