Antibodies against the 52-kd Ro(SS-A) protein are significantly associated with the primary Sjogren's syndrome (pSS). A small proportion of patients suffering from primary biliary cirrhosis (PBC) with secondary Sjogren's syndrome (PBC/SS) who are serologically characterized by antimitochondrial type 2 antibodies also express anti-52-kd Ro(SS-A) antibodies. The primary B-cell-derived antigenic responses by autoimmune sera were analyzed in both entities using truncated recombinant proteins to examine whether different epitopes are associated with these diseases. Sera were collected from 25 patients with pSS and 9 anti-52-kd Ro(SS-A)-positive patients suffering from PBC/SS. B-cell epitope mapping was performed using different 52-kd Ro(SS-A) fusion proteins in enzyme-linked immunosorbent assay (ELISA) and immunoblotting. Sera from patients with pSS showed the broadest reactivity against antigenic epitopes at AA 153-245 compared to the significantly limited reactivity against AA 228-245 of sera from patients with PBC. B-cell epitopes within AA 190-245 represent immunodominant epitopes recognized by pSS sera in a significantly higher degree than by PBC sera, which react predominantly with AA 228-245 (P < .0001). Anti-La(SS-B) antibodies were significantly associated with anti-52-kd Ro(SS-A) in sera from patients with pSS compared with PBC patients (P < .025). Thus, the antibody response to 52-kd Ro(SS-A) in PBC appears to be induced differently than in pSS. Although a limited immune response to 52-kd Ro(SS-A) occurs in PBC/SS patients, a more extended epitope spreading is evident in patients with pSS.