The role of antibody-dependent cellular cytotoxicity (ADCC) in host defense against tumor growth and metastasis was investigated with MH134, an MM antigen-positive murine hepatoma, and MH134-M, a variant with enhanced tumorigenesis and metastasis, in syngeneic C3H/HeN mice. When inoculated subcutaneously into C3H/HeN mice, MH134-M tumors grew more rapidly than did MH134 tumors and consistently metastasized to the draining lymph nodes, whereas MH134 tumors did not. Also, MH134-M exhibited a significantly greater lung colonization potential than did MH134, when inoculated intravenously into C3H/HeN mice. In BALB/c nu/nu mice, however, solid MH134 tumors grew and metastasized to the same extent as MH134-M, indicating that there is no significant intrinsic difference between these two tumor lines in proliferative or metastatic capacity. Enzyme-linked immunosorbent assay (ELISA) and immunoblotting, performed after SDS-PAGE analysis of cellular extracts with a monoclonal antibody (MAb) that recognizes a part of the MM-antigen, revealed that the cells of MH134-M lack at least a part of the MM antigen. Sera of C3H/HeN mice bearing solid MH134 tumors were found to contain anti-MM-antigen antibodies, when tested by immunoblotting of SDS-PAGE-developed materials. Cytotoxicity testing in which thioglycollate-induced peritoneal macrophages were used as effector cells revealed that antibodies present in sera strongly induced ADCC to MH134 but not to MH134-M. On the other hand, sera of MH134-M tumor-bearing C3H/HeN mice neither contained anti-MM-antigen antibodies nor induced ADCC to MH134 or MH134-M tumor cells. Intravenous injection of carrageenan into C3H/HeN mice bearing solid MH134 tumors significantly enhanced tumor growth, whereas the growth of subcutaneously injected MH134-M tumors was not influenced by this treatment. These results suggest that the enhanced tumorigenesis and metastasis of the MH134-M line in C3H/HeN mice are based, at least in part, on significant loss of the MM antigen and the resultant inability to induce ADCC-triggering antibody production during tumor growth.