Tumor necrosis factor-alpha (TNF-α) has been implicated in several late consequences of trauma such as sepsis, multiple organ failure, and ischemia-reperfusion injury. However, no data are available to indicate whether TNF-α is involved in the initial pathophysiologic response to trauma. To address this issue, serum TNF-α was determined (by ELISA) longitudinally (first blood sample on admission) in 100 randomly selected trauma patients admitted to the emergency department and trauma division at Jefferson Medical Center, Philadelphia. The TNF-α levels were detectable at one or more time points in 35 patients. Mean values tended to be elevated (50.3 ± 11.5 pg/mL) during the first 5 days, but this trend did not differ statistically from that in healthy controls (n = 12) and did not correlate with the severity of injury (Injury Severity Score and Glasgow Coma Scale score). The TNF-α response was not dependent on the mechanism and site of injury, the presence of shock (systolic blood pressure <90 mm Hg), and the need for emergent surgery. Also, serum TNF-α levels were not significantly elevated in patients who subsequently developed multiple organ failure (n = 4), septic shock (n = 5), or both (n = 3). Taken together, these data do not support a role for circulating TNF-α in the initial acute inflammatory response to trauma.