The serum from 109 traumatized patients was examined for immunosuppressive activity which might explain diminished host immune responsiveness following operative or accidental injury. Twenty-eight fo 31 (90%) severely tralmatized patients, 25 of 60 (42%) moderately traumatized patients, and 0 of 18 minimally traumatized patients developed serum which suppressed the response of normal human lymphocytes to phytohemagglutinin. The degree and duration of serum immunosuppressive activity paralleled the severity of the clinical course but did not correlate with serum cortisol or barbiturate levels. Suppressive sera were not cytotoxic. The immunosuppressive factor(s) was contained in a low molecular weight (less than 10,000 daltons) peptide fraction and was present in 5--10 times the amount recoverable from normal serum. By size and activity the trauma serum factor resembled immunoregulatory alpha globulin, a naturally-occurring serum inhibitor of T-lymphocyte reactions. Thus, depressed immunoreactivity following trauma may be due in part to high concentrations of an endogenous immunosuppressive polypeptide.