Cells of the human mononuclear phagocyte system have recently been shown to possess cytophilic IgO molecules that promote phagocytosis of staphylococci bearing cell-wall protein A. In the present study, the possible mediation of a cytotoxic response to 51Cr-labeled sheep erythrocytes coated with protein A by cytophilic antibodies on human peritoneal macrophages was evaluated. The target cells were readily lysed by peritoneal macrophages. Cytotoxicity was blocked by pretreatment of macrophages with soluble protein or with anti-Fc F(ab′)2, fragments. In contrast, cytotoxicity was not affected by cytochalasin B; this finding suggests that cytolysis is an extracellular event. Perturbation of cytophilic IgO with particle-bound protein A elicited a chemiluminescent response from peritoneal macrophages; however, experiments with scavengers of reactive oxygen species indicated that toxic oxygen radicals may not be required for cytotoxicity. The results indicate that cytophilic antibody-mediated cytotoxicity may contribute to cellular injury as well as host-defense aspects of the inflammatory process.