AbstractThe involvement of rheumatoid factor (RF)‐secreting cells in normal immune responses was examined by screening hybridomas derived from 129/Sv mice during primary and secondary immune responses against foreign proteins. No RF‐secreting cells were detected during primary responses, but up to 10% of the total number of clones obtained during secondary responses produced IgM with anti‐IgG activity. Like typical mouse RF, these anti‐IgG autoantibodies had a strict isotypic specificity, mostly for IgG1, and a much stronger avidity for immune complexes than for native IgG. The selective activation of IgG1‐specific RF during these secondary immune reactions was not due to fortuitous antigenic similarities between mouse IgG1and the antigens used for immunization, nor did it result from the use of adjuvants for priming, or from contamination of antigen preparations with lipopolysaccharide. It is therefore concluded that, in the 129/Sv mouse, RF production during secondary immune responses is a physiological p