Experimental evidence is accumulating to support a central role for cytokines in the pathophysiology of hemolytic transfusion reactions. The production of tumor necrosis factor, interleukin-8, and monocyte chemoattractant protein occurs in whole blood in response to ABO incompatible red cells, a model of acute hemolytic transfusion reactions. Peripheral blood mononuclear cells may produce interleukin-1 beta, tumor necrosis factor, interleukin-8, monocyte chemoattractant protein, and interleukin-1 receptor antagonist in response to IgG-coated red cells, a model of delayed hemolytic transfusion reactions. Cultured umbilical vein endothelial cells respond to conditioned plasma from ABO-incompatibility reactions by expressing the procoagulant tissue factor and the leukocyte adhesion molecules ELAM-1 and ICAM-1. These in vitro endothelial cell responses can be inhibited by neutralizing antibodies to tumor necrosis factor, suggesting that TNF may have a central role in intravascular coagulation and end-organ injury that may occur in acute hemolytic transfusion reactions.