Carbonic anhydrase (CA) is an extremely basic zinc metalloenzyme with a wide phyletic distribution, and the enzyme is important for the regulation of acid-base status. A novel autoantibody reactive with carbonic anhydrase was demonstrated. Several different classes of CA are known in mammals. Using the immuno blotting method and and immun-dot analysis, we found this autoantibody to be reactive with CA in the sera from patients with Sjögren's syndrome (20.8%), including a patient with Sjögren's syndrome and renal tubular acidosis, and in patients with systemic lupus erythematosus (31.6%). The autoantibody varied in the extent of its cross-reactivity among human CA I (or B), human CA II (or C), bovine CA I, bovine CA II, rabbit CA, and dog CA. The titers continued to float and tended to parallel disease activity. Positive reactivity of autoantibody was observed on eccrine sweat glands and the distal tubules of the kidney by the indirect immunofluorescent method.