Sera from 7 of 37 patients with systemic sclerosis (SS) were found to markedly enhance cytotoxicity in several established human target cell lines when co-cultured with normal human peripheral blood mononuclear cells (PBM). Fractionation studies indicated that the cytotoxicity-inducing activity resided in the IgG-containing fractions of serum and that the effector cells were Fc-receptor positive. By contrast, sera from 27 normal controls produced little or no cytotoxicity when co-cultured with the same target cell lines and normal PBM. Any slight enhancement of cytotoxicity that occurred with a single target cell line was, on fractionation, either labile or associated with albumin containing fractions. These findings raise the possibility that antibody-dependent cellular cytotoxicity (ADCC) could provide a pathogenetic mechanism in some patients with SS.