The objective of this study was to determine the prevalence of antibodies against alpha-fodrin (alpha-fodrin) of the immunoglobulin G (IgG) isotype in Sjögren's syndrome (SS), as defined by European Community Study Group (ESG) and ESG-modified criteria. We arrived at the prevalence and mean concentrations of IgG anti-alpha-fodrin antibodies using enzyme-linked immunosorbent assay (ELISA) in 507 patients with SS, primary SS (pSS), and secondary SS (sSS), classified according to either the ESG or the ESG-modified criteria. IgG anti-alpha-fodrin antibodies were detected in 6/507 (1.2%) and 4/228 (1.7%) of the SS group, according to the ESG or ESG-modified criteria, respectively. Similar prevalence was found for patients with pSS or sSS. Anti-Ro/SSA antibodies were present in 151/409 (36.9%) vs. 149/213 (70.0%) of the SS group, 85/195 (43.6%) vs. 83/101 (82.2%) of the pSS group, and 66/214 (30.8%) vs. 66/112 (58.9%) of the sSS group. Anti-La/SSB antibodies were detected in 77/403 (19.1%) vs. 73/212 (34.4%) of the SS group, 47/194 (24.2%) vs. 45/101 (44.5%) of the pSS group, and 30/209 (14.3%) vs. 28/111 (25.2%) of the sSS group. No clinical associations were found. Only two IgG anti-alpha-fodrin-positive sera were anti-Ro/SSA-negative. We conclude that IgG antibodies against alpha-fodrin are present in a small percentage of people with SS, pSS, and sSS. The lower prevalence in patients classified according to the ESG criteria reflects the lower specificity of these criteria. IgG anti-alpha-fodrin antibodies can be detected in some SS patients whose sera do not contain anti-Ro/SSA antibodies.