To gain insight into a possible role for antibody-dependent cell-mediated cytotoxicity in vivo, we examined the ability of leukocytes from 28 patients with primary immunodeficiency and from 20 normal controls to lyse three different types of antibody-coated targets in vitro. Mean cytotoxic indices +/-1 SD elicited by unfractionated mononuclear cells from normal controls were 28.74+/-13.26 for human HLA antibody-coated lymphocyte targets, 42.79+/-8.27 for rabbit IgG antibody-coated chicken erythrocyte targets, and 47.58+/-10.34 for human anti-CD (Ripley)-coated O+ erythrocyte targets. Significantly (P=<0.05) lower than normal mean cytotoxic indices against lymphocyte targets were seen with effector cells from 10 patients with X-linked agammaglobulinemia (3.7+/-4.33), in 10 with common variable agammaglobulinemia (16.05+/-7.74), in 3 with immunodeficiency with hyper IgM (18.41+/-4.88), and in 2 with severe combined immunodeficiency (3.94+/-0.3). Antibody-dependent cytotoxicity against chicken erythrocytes was significantly (P=<0.05) lower than normal only in the common variable agammaglobulinemic group (33.33+/-12.3) and against human erythrocytes only in the common variable (34.36+/-9.59) and hyper IgM (27.54+/-0.66) groups. Rosette and anti-F(ab')(2) depletion studies with normal leukocytes indicated that a nonadherent, nonphagocytic, non-Ig-bearing, non-C receptor-bearing, Fc receptor-bearing lymphocyte was the only effector capable of lysing HLA antiboyd-coated lymphocyte targets. Patients with infantile X-linked agammaglobulinemia and severe combined immunodeficiency appear to have a marked deficiency in this type of effector cell function.