The first step in macrophage-mediated tumor lysis, effector-target contact, was studied in a C3H/He mouse-MM46 syngeneic tumor system in which antibody-dependent tumor lysis by macrophages (ADMC) was observed in vitro. Various lectins were tested for the ability to mediate the contact between effector macrophages and target tumor cells. Several lectins, such as wheat germ agglutinin (WGA), concanavalin A, phytohemagglutinin, and pokeweed mitogen, were found to induce this contact, but only WGA also induced tumor lysis by macrophages. Both this lectin-dependent cytolysis by macrophages (LDMC) and the cytoadherence between macrophages and tumor cells induced by WGA were inhibited by N-acetyl-glucosamine, a sugar specifically recognized by WGA. In the LDMC reaction, macrophages in the presence of WGA could kill other syngeneic and allogeneic tumor cells but not normal thymus or spleen cells. These findings suggest that WGA is a ligand in macrophage-mediated cytolysis, inducing the binding of effector cells to target cells that triggers off lysis of the target cells. Comparative studies on the mechanisms of cytolysis involved in LDMC and ADMC showed that ADMC, but not LDMC, was inhibited by aggregated immunoglobulin and by protease pretreatment of macrophages. Thus, the mechanisms of recognition in LDMC an ADMC are different, but both ligands can induce the lytic reaction.