The production of antibodies that react with the Fc fragment of IgG, i.e., rheumatoid factors (RF), is now regarded as a normal host immune response. It is not clear, however, if such putative physiologic RF are different from their counterparts which characterize pathologic states like rheumatoid arthritis (RA). Using Staphylococcus aureus Cowan I as an in vitro stimulant of RF production, we now report that the IgM-RF secreted by blood mononuclear cells obtained from healthy newborn infants and healthy adults can be distinguished not only from classic monoclonal RF and polyclonal RA serum RF, but also from the RF secreted by blood mononuclear cells obtained from RA patients. Whereas the Fc-binding activity of all RF secreted in vitro was easily inhibited by aggregated human IgG, only the RF produced by the normal umbilical cord cells and the normal adult cells were inhibited by monomeric Fc(IgG). The normal RF were also selectively inhibited by monomeric rabbit and guinea pig (Fc(IgG). The RF secreted by umbilical cord blood cells utilized lambda and kappa light chains, with a disproportionate use of lambda light chains relative to the total IgM secreted. Together, these data provide evidence for distinct subsets of RF in health and in disease.