Skin testing with four recall antigens was performed serially in 21 patients after a major thermal burn. We looked for a correlation between the occurrence of anergy, the presence of immunosuppressive serum, and the impairment of the lymphocyte-proliferative response to phytohemagglutinin (PHA). Serum cortisol, endotoxin, and prostaglandin E2 (PGE2) levels were also measured in the serum or plasma. When anergy developed, it became apparent early in the course of the illness. It did not correlate closely with the severity of the burn, but was associated with mortality. There was a good correlation between anergy and coexisting serum suppression of lymphocyte activation in vitro. This serum immunosuppressive activity was not related to serum cortisol, PGE2, or plasma endotoxin levels. Anergy also correlated with coexistent impairment of patient peripheral blood lymphocyte activation by PHA. These results suggest that both immunosuppressive serum and an impaired lymphocyte response to mitogens are associated with anergy in burn patients and confirm that the development of anergy is an index of poor prognosis.