Although antibodies have been assumed to bind a specific antigen, evidence exists showing that a single antibody can bind to multiple unrelated antigens. We previously studied a human monoclonal antibody expressing a mutated form of the V_H3–73 gene and displaying anti‐tubulin activity in a patient suffering from an immunocytic lymphoma. Despite its expression of a V_H3 family member, this immunoglobulin failed to react with protein A (SpA), suggesting that somatic mutations could account for its change in specificity. To examine this possibility, we produced recombinant Ig expressing germ‐line (IgMκ‐Germ) or the mutated form (IgMκ‐PER) of the V_H3–73 fragment. Comparison of the respective affinities of the two Ig demonstrated that IgMκ‐Germ restores its SpA‐binding capacity, and shows a moderate decrease in its affinity for tubulin. Interestingly, IgMκ‐Germ displayed polyreactive specificity for different autoantigens, which contrasted to the monospecific binding of IgMκ‐PER to tubulin. These results suggest that the monoreactive IgMκ‐PER antibody may be derived from a natural polyreactive antibody through somatic mutation. In addition, both temperature modification and mild denaturation succeeded in recovering the polyreactivity of IgMκ‐PER, which favors the view that conformational modifications of the tertiary structure of antibodies may play a key role in the genesis of polyreactivity.