This study determines the antigenic regions of the nRNP C lupus autoantigen.Twenty-one anti-nRNP C sera, six patients with other autoimmune serology, and five normal control sera were assessed for binding with the overlapping octapeptides of the nRNP C protein. Column absorptions were conducted to assess the percentage of the anti-nRNP response which was directed against one major epitode of nRNP C:Eleven regions of nRNP C are bound in different combinations by anti-nRNP C patient sera. Neither normal controls nor patients without anti-nRNP C antibodies significantly bind any regions of nRNP C: The antigenic region spanning amino acids 117-126, PAPGMRPP, is recognized by all twelve Sm, nRNP precipitin positive patients tested. Indeed, from 14 to 32% of the anti-nRNP reactivity in Sm, nRNP precipitin positive patient sera is directed against PAPGMRPP: All of these patients also bind a very similar sequence which is repeated three times in the Sm B/B' protein. Patients sera with only anti-nRNP antibodies, however, do not recognize this proline rich sequence as antigenic.This elucidation of the specific areas of nRNP C which are important in the autoantigenicity of nRNP C will hopefully lead to a better understanding of the involvement of these autoantibodies in the etiology and pathogenesis of SLE.