The present report demonstrates that cells expressing idiotypic determinants on their surfaces can be specifically destroyed by anti-idiotypic antibodies acting as inducers of antibody-dependent cell-mediated cytotoxicity. Lysis of surface-idiotype-positive hybridoma cells was effected by mouse spleen cells, mouse peritoneal cells, or human blood mononuclear cells, in the presence of anti-idiotypic antibodies. In order for lysis to occur, the simultaneous presence of Fc receptor-bearing cytotoxic cells and anti-idiotypic antibodies was required. Specificity of lysis was conferred by the anti-idiotypic antibody. Hybridoma cells expressing a different idiotype could not be lysed. Anti-idiotypic antibody-dependent cell-mediated cytotoxicity against 51Cr-labeled cells expressing a particular idiotype could be induced by the specific anti-idiotypic antibodies and inhibited by unlabeled idiotype-positive cells or by idiotype in a soluble form. Cytotoxicity could not be inhibited by the presence of bystander cells or monoclonal antibodies expressing a different idiotype. It is proposed that ADCC lysis of idiotype-positive cells has important implications for understanding the regulation of immune responses by an idiotype-anti-idiotype network. This cytolytic pathway provides an extremely specific and effective mode of control of idiotype-positive cells by anti-idiotype antibody. Previous observations that an intact Fc fragment was necessary for anti-idiotype antibodies to exert suppressive effects in vivo further support this hypothesis.