Sera from 42 patients with systemic lupus erythematosus (SLE) and precipitating antibody to the La/SSB antigen contained 80,000 to 28,800,000 times the minimum detectable binding activity (units) in a solid phase ELISA assay using purified La/SSB antigen. Three normal sera (of 40 tested) had 7,200,21,600 and 21,100 units, respectively, while the log average of the 40 normals was 270 units. Binding activity in normal sera was in the F(ab')2 fragments of IgG, inhibited by purified La/SSB antigen, and bound the major La/SSB peptides. The average apparent relative binding affinity to La/SSB in normal donors was 10-fold lower than in SLE patients with anti-La/SSB precipitins. Analysis of other SLE sera revealed a high incidence of anti-La/SSB in association with anti-Ro/SSA precipitins.