We have detected circulating IgG antibodies that bind with high affinity to human umbilical vein endothelial cells in 74% of patients with systemic lupus erythematosus (SLE), 30% of those with scleroderma and 28% of those with rheumatoid arthritis. IgG binding was F(ab) mediated, and did not involve immune complexes. Anti-endothelial IgG were apparently unrelated to other circulating autoantibodies, including anti-cardiolipin or antiDNA IgG. Bound IgG from SLE or scleroderma patients was displaced by IgG from certain unrelated patients whereas others were ineffective. Anti-endothelial cell IgG from all sera tested were adsorbed by human dermal fibroblasts; erythrocytes and leucocytes each adsorbed a fraction of the activity. Purified IgG did not induce complement-mediated cytotoxicity. We conclude that a discrete group of IgG antibodies is common in connective tissue disease patients, reacts predominantly with endothelial cells and dermal fibroblasts, and may be important in the pathogenesis of vascular damage.