Sera from 35 patients with systemic lupus erythematosus were examined for a cytotoxic effect on human umbilical vein endothelium. Although none of these sera produced direct cytotoxicity of 51Cr-labelled endothelial cells, even with added complement, 3 sera regularly produced increased 51Cr release when co-cultured with endothelial cells and normal human peripheral blood mononuclear cells. The effector cells involved in this cytotoxicity possessed Fc-receptors but were non-T and non-adherent while fractionation studies indicated that the responsible serum factor(s) was IgG, probably in the form of immune complexes of small size. Control studies, using sera from both 27 normal controls and 19 patients with either diabetes or extensive atherosclerotic vascular disease failed to reveal any similar cytotoxicity. Two of the 3 patients, whose sera produced this antibody-dependent cellular cytotoxicity, had had clinical episodes of major vascular thrombosis, raising the possibility that the cytotoxicity might provide an additional pathogenic mechanism in certain patients with systemic lupus erythematosus.