Objective: To study whether the endotoxin responsiveness of peripheral blood mononuclear cells correlates with the severity of injury in trauma patients. Design: Prospective, observational study, Setting: University trauma center. Patients: Fifty-nine patients with blunt trauma (Injury Severity Score [ISS] 4 to 57 points). Interventions: Standard emergency department care, surgical care, and postoperative intensive care unit treatment, Measurements and Main Results: Whole blood and serum were obtained 94 +/- 89 (SD) mins post trauma (day 0) and during a 14-day period postinjury, Endotoxin-induced tumor necrosis factor-alpha (TNF-alpha) synthesis of peripheral blood mononuclear cells ex vivo was tested using a whole blood assay, Serum samples were assayed for TNF-alpha concentrations, A reduced capacity of whole blood to produce TNF-alpha ex vivo with endotoxin treatment was found to be closely correlated with the ISS, The capacity to produce TNF-alpha on endotoxin stimulation of whole blood from patients with an ISS greater than or equal to 16 points was depressed immediately after trauma and did not reach normal values during the observation period, In patients with an ISS >22 points, maximum depression of the capacity of whole blood to produce TNF-alpha occurs within 100 mins post injury, In contrast, in patients with an ISS <22 points, maximal depression of whole blood TNF-alpha production occurs with a delay of 24 to 48 hrs after trauma, Based on pre- and postoperative values, primary surgical intervention caused a decrease of the endotoxin stimulated TNF-alpha production of whole blood in the latter patient subgroup, as well as in the entire patient population (ISS 4 to 57) when secondary surgical treatment was neccesary 5 to 13 days after trauma. Conclusions: The extent of traumatic tissue damage leads to a graded depression of immunocyte function and appears to be amplified by surgical treatment. The endotoxin responsiveness of peripheral blood mononuclear cells displays a functional marker of the anatomically defined severity of injury and gives insights into the regulation of immunocyte function after severe blunt trauma.