Previous investigations have shown that human K lymphocytes carry out antibody-dependent cell-mediated cytotoxicity (ADCC) toward a variety of target cell types excluding allogeneic erythrocytes (RBC). More recently, however, evidence has been presented which indicates that certain human erythrocyte-antibody combinations are actually quite susceptible to K lymphocyte ADCC. These targets, which include papain-treated CDe/EDE RBC or-D-/-D-cells each sensitized with small amounts of anti-D IgG and normal CDb/EDE RBC sensitized with high titer anti-D or anti-CD IgG sera, possess as a common feature" clustered" surface I&. This study examined K lymphocyte ADCC to these same targets and simultaneously measured the amount of target bound IgG by'261-Staphylococcal protein A (SPA) assay. CDC/CDE erythrocytes, which have dispersed D antigens, were coated with approximately 9000, 5000, and 1500 anti-D IgG/cell but were lysed poorly, if at all, by lymphocytes (696, 1%, and 0%" Cr release, respectively). These same targets pretreated with papain to cluster D antigens were quite sensitive to lymphocyte ADCC when coated with the same numbers of IgG molecules (81%, 72%, and 34%'lCr release, respectively). Similarly,-D-/-D-RBC, which also possess clustered anti-D IgG, were lysed significantly by lymphocytes (42% 61Cr release with 8400 IgG/cell and 28%" Cr release with 5400 IgG/cell). Loss of sialic acid, and thus decrease in surface charge, from enzyme-treated RBC targets correlated roughly with enhanced susceptibility to lymphocyte ADCC for some enzymes (papain and neuraminidase) but not for others (trypsin). Osmotic fragility of enzyme-treated cells was normal and does not account for their sensitivity to lysis. These data suggest that the spatial arrangement of IgG on the target cell surface may play an important role in determining whether K lymphocytes express Fc receptor activity in terms of binding and lysing antibody-coated RBC.