Abstract: A method is described for the differential diagnosis of rheumatological diseases. Sera from patients with SLE; MCTD, and RA are screened for antibodies directed against RNA polymerase II using a solid phase immunoassay. Significant levels of the antibodies were detected with sera of all SLE and MCTD patients and in 78% of the RA patients. No detectable anti-RNA polymerase I antibodies were detected in the sera of healthy individuals.Sera from patients with SLE contained immunoglobulins directed against the S3 subunit of RNA polymerase I, as well as antibodies to the S2 or S5 subunits, RA patient's sera contained antibodies only to S3 while MCTD patients sera contained antibody to S4 in addition to antibody to the S3 and S5 subunits. The identification of specific reaction patterns of the antibodies with the individual subunits of the RNA polymerase I is indicative of a particular class of rheumatological disease.