The phagocytosis of IgG-coated erythrocytes (EIgG) has been shown to augment the bacterial lipopolysaccharide (LPS)-stimulated increase in serum tumor necrosis factor- (TNF-) levels. The present study evaluated the role of Fc-receptor (FcR) signaling and complement activation in the effect of EIgG on the TNF- response to LPS. The role of FcR was determined using FcR -chain knockout mice that lack functional FcRI and FcRIII. In wild-type animals, EIgG caused a 16-fold augmentation of the serum TNF- response to LPS, whereas there was no augmentation in the FcR-deficient animals. Heat-damaged erythrocytes also augmented the TNF- response to LPS. This effect was absent in FcR-deficient animals. An IgG antibody against heated erythrocytes was detected in mouse serum. The complement activation caused by EIgG had little effect on the LPS-stimulated increase in serum TNF- levels as indicated by activation of complement with cobra venom factor or IgM-coated erythrocytes as well as studies with C5-deficient mice. These results indicate that FcR signaling primarily mediates the augmented serum TNF- response to LPS caused by EIgG.