CD5+ lymphocytes constitute a major subset of the normal human B cell repertoire. We found here, by transformation with EBV and limiting dilution analysis, that the majority of CD5+ B cells from healthy subjects are committed to the production of antibodies with rheumatoid factor-like activity. By fusing the EBV-transformed cells generated from CD5+ B lymphocytes with human-mouse heterohybrid cells, we constructed continuous cell lines producing mAb. These mAb bound not only to the Fc fragment of IgG but also at varying degrees to other self-Ag, such as ssDNA, thyroglobulin, and insulin, as well as to exogenous Ag, such as tetanus toxoid, LPS from Gram-negative and polysaccharides from Gram-positive bacteria. Competitive inhibition studies revealed that although each of the mAb reacted with the Fc fragment of IgG, their functional affinities for other Ag varied by as much as 1000-fold. Our studies argue that broad polyreactivity is an inherent property of the antibodies produced by CD5+ B lymphocytes and that these antibodies may be what has been referred to as the "natural antibodies" of the serum.