Autoimmune diseases such as Sjögren's Syndrome and systemic lupus erythematosus (SLE) are characterized by serum autoantibodies against protein components of small cytoplasmic ribonucleoproteins (scRNPs). The origin and regulation of these anti-Ro/SS-A and anti-La/SS-B antibodies is not well understood. Regular co-occurrence of these two autoantibodies in humans together with murine studies on antibody responses against scRNPs after immunization suggest a role for scRNPs as common antigen. We sought additional evidence for this hypothesis in a longitudinal serological study of patients with SLE. Quantitative measurement of the antibody responses against Ro/SS-A and La/SS-B proteins and for comparison to dsDNA in 852 serum samples was performed. These samples were collected from nine patients during an average observation period of more than 10 years. A significant and strong correlation between the two anti-scRNP responses emerged during 90% of follow-up. In contrast, correlation of anti-scRNP with anti-dsDNA responses was remarkably absent in the same patients. Our results confirm the unique relationship between anti-Ro/SS-A and anti-La/ SS-B responses and could thus be interpreted as support for a model wherein induction and perpetuation of autoantibody production is dependent on scRNPs containing both proteins as antigen.