The participation of prostaglandin E in the regulation of the immune response via suppressor cell activation, and the release of large quantities of these prostaglandins as a result of thermal injuries, are both (separately) well documented. In this report, we present evidence that prostaglandin E plays an important immunologic role following thermal injuries. The concentration of PGE in sera from patients with major burn injuries is generally high (1,000–3,000 pg/ml), and these same sera are often significantly suppressive to in vitro lymphocyte responsiveness. We have documented the ability of PGE (both that which is commercially synthesized, and that isolated in fractions obtained from burned patient sera by column chromatography) to suppress mixed lymphocyte cultures, and show that such suppression can be blocked by either delipidation of serum fractions, or by the addition of monospecific anti-PGE to the cultures. We also report evidence suggesting the existence of a serum protein with a molecular weight of approximately 5,000 daltons which appears to be necessary for the expression of the immunosuppressive properties of PGE contained in patient sera.