Sera from patients with systemic lupus erythematosus (SLE) were shown to react with both ubiquitin and a synthetic fragment of it (residues 22-45) in an ELISA and with ubiquitin in immunoblotting experiments. Close to 80% of lupus patients possessed ubiquitin antibodies, whereas only 55% of them possessed native DNA antibodies, a marker of SLE. Less than 16% of patients with other rheumatic autoimmune diseases possessed antibodies to ubiquitin. Our results indicate that the combined measurement of antibodies to native DNA and to ubiquitin could appreciably increase the detection of SLE cases (up to 85% in our study). It is suggested that ubiquitin, a heat shock protein, could be involved in antibody formation against ubiquitin-protein conjugates present during cellular injury and that this represents a major characteristic of the autoimmune response in SLE.The immunopathology and etiology of systemic lupus erythematosus (SLE) have been intensely investigated in recent years. The most striking feature of rheumatic diseases, and of SLE in particular, is the large variety of induced clinical manifestations and the wide spectrum of autoantibodies found to react with different constituents of normal cells. The antigenic targets of autoantibodies found in SLE include a number of nuclear components (DNA,