Concentrations ranging between 0.01 and 10 pg per cell of certain monoclonal antibodies (MAbs) are shown to constitute 4-hr 50% lethal doses for tumor cells mixed with human effectors of antibody-dependent cellular cytotoxicity (ADCC). This efficient and rapid tumor cell lysis is achieved at low effector cell levels (effector:target ratios, less than or equal to 25:1) at which the effectors are nonadherent peripheral blood leukocytes (PBL) enriched by density centrifugation. Comparable MAb-mediated ADCC efficiency has not been reported previously, probably because most MAbs (e.g., 10 of 13 tested in this study) are typically inefficient or completely inactive in mediating ADCC, even at 100-fold greater concentrations. By analyzing the ADCC efficiencies of several MAbs specific for murine cell surface alloantigens, it is shown that murine IgG2a and IgG3 MAbs and a rat IgG2b MAb are very efficient mediators of ADCC. However, ADCC efficiency was found not to correlate strictly with subclass, since 4 of 6 murine IgG2a MAbs tested were completely inactive, even though they all bound the target cells readily. It is shown that the relative differences in ADCC efficiencies are not accounted for directly by antibody affinity for antigen; one MAb was very efficient in ADCC but had demonstrably low antigen affinity, while a second MAb showed no ADCC activity in spite of its high affinity for the same target antigen. These results point to other experimentally testable properties of MAbs and of MAb-antigen complexes which may be critical for efficient ADCC reactions. This study underscores an important immunotherapeutic value which certain MAbs potentially have for mediating tumor cell lysis: in low concentrations (and without toxic drug modification), some MAbs efficiently mediate the lysis of tumors by ADCC, which itself is as effective as other immune lytic processes but which requires no prior immunological education of effector cells.