Treatment of mice with Bacille Calmette-Guérin (BCG) or C parvum activates their peritoneal macrophages to release increased amounts of H2O2, and thereby to lyse extracellular tumor cells, in response to a pharmacologic agent, phorbol myristate acetate (PMA) (1-3). In the present study, the same bacterial vaccines activated peritoneal cells to become cytolytic to lymphoma cells sensitized with alloantiserum, in the absence of PMA. Resident peritoneal cells, or those elicited with thioglycollate broth, were ineffective, not only in PMA-induced lysis, but also in antibody-dependent lysis of tumor cells. The cytolytic effect of BCG peritoneal cells toward sensitized tumor cells appeared to be mediated mostly by macrophages. Cytotoxicity was immunologically specific, contact dependent, rapid, and efficient. Phagocytosis of intact tumor cells was not involved. Alloantiserum-dependent cytolysis was specifically blocked by the Fab fragment of a monoclonal antibody directed against the trypsin-resistant macrophage Fc receptor (FcR II). Thus, tumor cells coated with homologous immunoglobulin interact with FcR II on activated macrophages to trigger an extra-cellular cytolytic response.