A new antigen (Su) from calf thymus nuclear extract that reacts with sera from patients with systemic lupus erythematosus (SLE) is described. Antibodies to Su, demonstrated by immunodiffusion, were most frequently found in patients with a diagnosis of probable or definite SLE. Thirty-seven percent of patients with Su antibodies and a diagnosis of SLE were positive for antinuclear antibodies by indirect immunofluorescence, but lacked specific antibodies previously associated with SLE. Patients with Su antibodies exhibited a higher frequency of Raynaud's phenomenon, but exhibited a lower frequency of malar rash, alopecia, and arthritis when compared with SLE patients in previously published reports. The Su antigen is weakly acidic, heat-stable at 37 degrees C, heat-sensitive at 56 degrees C, resistant to DNase and RNase, but sensitive to trypsin. Its molecular weight approximated 154,000 daltons by Sepharose chromatography. The Su antibody may be associated with a subset of SLE patients with distinct clinical features, and may serve as a serologic marker for patients who are positive for fluorescent antinuclear antibodies but have no other detectable SLE-associated antibodies.