IgM antibodies, by themselves unable to induce human K-cell-mediated cytotoxicity, enhanced the lysis of TNP-coated bovine erythrocytes (TNP-Eb) induced by suboptimal concentrations of IgG antibodies. The antibodies used were directed against either TNP or intrinsic Eb antigens. The best enhancement of antibody-dependent cell-mediated cytotoxicity (ADCC) was obtained when IgG and IgM antibodies had different specificities. IgM antibodies with specificity similar to that of the IgG antibodies often inhibited rather than enhanced cytolysis. By using 125I-labelled anti-DNP IgG, the number of IgG/TNP-Eb was determined. Under the present conditions, at least 9000 IgG molecules/TNP-Eb were required for K-cell-mediated lysis in the absence of IgM. In the presence of IgM antibody concentrations optimal for enhancement of ADCC, the minimal number of IgG molecules required for induction of ADCC was 30-100 times lower. No enhancement of cytotoxicity was seen with more than the optimal concentration of IgM even when IgG binding to the target cells was not reduced by IgM. This suggested that induction of ADCC was dependent on contiguous IgG-Fc receptor interactions, which were inhibited owing to steric hindrance by excessive amounts of IgM in the critical contact areas between effector cells and target cells.