Patients, after major thermal injury, often develop multiple in vitro immunologic abnormalities. The etiology of these immune defects is unknown, although there is evidence suggesting that these defects may be the results of circulating suppressor substance(s). To evaluate the role of the local injury in the development of immune incompetence the biologic effect of blister fluid on control lymphocyte mitogenic response to PHA was studied. Blister fluid from 35 patients, mean burn size 29% (range, 1–85% TBSA) was added to a standard lymphocyte blastogenic assay, using various concentrations of PHA (from 0.5 μg to 40 μg per well). Eight of these 35 patients (23%) had blister fluid which suppressed the control lymphocyte blastogenic response greater than 50%. Two patients with suppressive blister fluids also had suppressive serum. In contrast, only two of the nine patients whose blister fluid was not suppressive had suppressive serum. This suppressive activity was not related to bacterial contamination nor to the presence of detectable levels of endotoxin.