The ability of sera from patients with SLE and similar connective tissue diseases to induce dysfunction of the receptor for DNA was studied. All SLE and MCTD sera studied resulted in marked inhibition of DNA receptor binding. Furthermore, the sera from a subgroup of patients with other rheumatic diseases and a surprisingly high percentage of asymptomatic relatives of SLE patients exhibited a similar effect. The humoral factors causing this defect were shown to be of at least three reactivities: (a) antibodies to DNA, (b) antibodies to histones, and (c) antibodies to the DNA receptor itself. The reactivity of anti-DNA and antihistone antibodies is dependent upon intact cell-surface DNA, and reconstitution experiments suggest that antihistone antibodies are reactive with histones complexed to this DNA, which in turn is bound to the DNA receptor. Cells with an antibody-induced DNA receptor defect are unable to bind DNA; the subsequent inability to degrade DNA may have important consequences in diseases such as SLE in which DNA-anti-DNA immune complexes are of pathogenetic significance.