The potential function of IgA anti-HIV antibodies in mediation of antibody-dependent cellular cytotoxicity (ADCC) was investigated in this study. Serum IgA isolated from HIV-seropositive subjects in stage B3 or C3 and from healthy seronegative individuals was compared to IgG and whole serum for the ability to mediate ADCC. Peripheral blood mononuclear cells isolated from uninfected donors were used as effectors against CEM-NKr cells chronically infected with the HTLV-IIIB strain of HIV-1. Whole sera, isolated IgA, and IgG from both groups of seropositive individuals were capable of significant ADCC lysis against infected CEM-NKr cells compared to identical preparations from seronegative individuals. In comparing ADCC activity between the two seropositive groups, IgG mediated higher mean ADCC levels in the C3 group at the two highest concentrations of antibody assayed (P < 0.03), whereas IgA mediated the highest mean ADCC levels in the B3 group at all concentrations. Secretory IgA (S-IgA) isolated from colostrum of HIV-infected women was also examined for ADCC capabilities against infected CEM-NKr cells. Significant differences were observed between ADCC mediated by S-IgA from seropositive mothers compared to seronegative mothers (P < 0.04), but the amount of lysis detected was not as great as that seen with serum IgA. The presence of IgG, serum IgA, and secretory IgA antibodies capable of mediating ADCC may be critical in maintaining a functional immune response in all stages of HIV infection.