The transfusion of incompatible red blood cells (RBC) rapidly results in the development of fever by an unknown mechanism. In this study, the human monocyte secretion of the endogenous pyrogens tumor necrosis factor (TNF) and interleukin-1 (IL-1) was measured. Exposure to human RBC sensitized with antibodies to D or Fya antigens induced the rapid secretion of TNF, but not IL-1. TNF secretion persisted when monocytes remained in contact with sensitized RBC, but returned to baseline several hours after removal of RBC. Thus, TNF secreted by monocytes may be a mediator of fever during the immune-mediated destruction of RBC in vivo.