Serum of patients with severe burns has the ability to suppress mitogen-induced lymphocyte proliferation. Edema fluid collected from the site of injury during resuscitation and at the time of fascial excision has also been shown to suppress this response. An animal model was designed to identify the onset time of the formation of suppressive factors, their potential site(s) of origin, and their route of entry into the systemic circulation. Femoral artery, saphenous vein, and lateral saphenous lymphatic vessels were cannulated in an anesthetized dog. Baseline samples were collected, the hind paw was subjected to scald injury, and samples were collected serially for up to 6 hours after burn injury. Tissue fluid beneath the scald injury was harvested at the end of the experiments. In the absence of significant serologic evidence for inhibition, lymph and tissue fluid exhibited early and prolonged suppression of mitogen-induced lymphocyte proliferation. We concluded that edema fluid capable of cell-mediated immune suppression forms early after thermal injury and that lymph generated from the site of burn injury is immunosuppressive.