The importance of tumor necrosis factor (TNF) in the pathophysiology of trauma and hemorrhagic shock is not known. In addition, TNF bioactivity may be modulated by soluble forms of the 55-kd and 75-kd membrane receptors (TNFR). This study was undertaken to determine circulating levels of TNF and TNFR after trauma. Nine severely injured male patients were studied. The mean age was 30 ± 10 years (range, 15-45). The mean Injury Severity Score (ISS) was 31.3 ± 17.6 (range, 10-59), and the mean Revised Trauma Score (RTS), 5.7 ± 2.2 (range, 0.7-7.8). Serum was obtained immediately upon arrival at our trauma center, within 1 hour of injury. The TNF and TNFR levels in the serum were measured using ELISA techniques. After trauma, 55-kd and 75-kd TNFR levels were significantly elevated above those of controls (6.99 ± 4.57 ng/ml and 5.42 ± 1.88 ng/ml, respectively, p < 0.01); TNF levels were not increased. Patient serum containing TNFR inhibited in vitro TNF cytotoxicity and correlated with 55-kd TNFR levels (p < 0.05). We conclude that TNF is a strong releasing factor for TNFR; the presence of TNFR may be indirect evidence that TNF is present after trauma, despite low measured levels. Both TNF and TNFR may be more important in trauma and hemorrhagic shock than previously thought. THE ROLE OF TUMOR NECROSIS FACTOR (TNF) in the pathophysiology of trauma and hemorrhagic shock remains unclear. Several animal studies have demonstrated systemic release of TNF after hemorrhagic shock. 1 • 2 However, previous human studies of both elective surgery and trauma have not demonstrated significant circulating levels of TNF. 3-5 Although the numerous functions of TNF have been extensively studied, there is a relative paucity of information regarding the regulation of TNF. In recent years, two soluble receptors for TNF (TNFR) have been identified. These soluble receptors have been found in the serum and urine of patients with chronic renal failure as well as in the serum and ascites of cancer patients. 6-8 These TNFR are shed or secreted from the extracellular segments of the 55-kd and 75-kd TNF membrane receptors and may be important in the regulation of TNF activity. 8-10 The TNFR are capable of binding TNF and preventing binding to cellular membrane receptors, thus decreasing the biologic effects of the cytokines. In vitro the TNFR have been found to inhibit the lytic activity of TNF on murine L929 and WEHI 164 cells. 8 • 10 In addition, TNFR inhibits in vivo necrosis of cutaneous