We have previously reported that severe burn injury was regularly accompanied by impaired lymphocyte responses to T cell mitogens, circulating suppressor lymphocytes, and serum factors suppressive of lymphocyte activation. However, in burned patients it was difficult to determine whether these manifestations of suppressed immunity were predictive of, or the result of, sepsis which was ubiquitous in this population. In an attempt to clarify this issue, we have studied 31 patients with multiple trauma (without burns) mean age, 31 years; average injury severity score, 22; range, 9–56; in whom sepsis was less common. Patients were tested for lymphocyte response to the T cell mitogens PHA and Con A, the percentage of circulating putative suppressor (OKT8) and helper (OKT4) T cells using monoclonal antibodies, circulating suppressor cell activity as revealed by functional assays, and serum suppression of lymphocyte activation. Patients were compared with ten normal volunteers (mean age, 32) studied simultaneously. Significant suppression (>50% compared with controls) in lymphocyte responses to mitogens 1 to 5 days after injury was seen in 12 patients, was accompanied by a shift in the ratio of helper (OKT4) to suppressor (OKT8) T cells (patients, 0.96:1; normals, 1.82:1; p < 0.01), and was followed by the appearance of significant (>50%) serum suppressive activity in six of the 12 patients. Circulating suppressor cell activity as revealed by functional assays was also seen early after injury in three of 12 patients. In the entire group of 31 patients mean suppression of lymphocyte PHA responses improved with time (1 to 5 day suppression, 35 ± 8%; 10 to 20 day suppression, 10 ± 6%; p < 0.005) but persisted in three patients, two of whom developed clinical sepsis and survived and one who died as a result of his injuries and sepsis. The degree of serum suppression seen early after injury in these patients correlated with the severity of trauma (r = 0.929), a finding supported by similar studies performed in 18 additional patients undergoing uncomplicated elective abdominal aortic aneurysm repair who showed minimal serum suppression of normal lymphocyte mitogen responses (14 ± 5%) postoperatively and no shift in the OKT4:OKT8 T cell ratio. We conclude that impaired lymphocyte function commonly follows serious injury and while it may predispose to sepsis it is not necessarily caused by it.