In vitro stimulation of lymphocytes from healthy donors with well-defined polyclonal B cell activators may elicit the production of rheumatoid factor (RF) as well as other autoantibodies. Antigen stimulation may also result in polyclonal B cell activation, but it is not known if RF production is a feature of this response. Therefore, peripheral blood mononuclear cells from 36 healthy volunteers previously immunized to tetanus toxoid (TT) were stimulated in vitro for 9 days with a conventional antigen, TT, or pokeweed mitogen, a standard polyclonal B cell activator. Culture supernatants were analyzed for total IgG, total IgM, and IgM RF by ELISA. TT-induced IgM RF production was observed in 10/36 experiments compared to 18/36 experiments in which cells were cultured with pokeweed mitogen, with a similar magnitude of response to these respective stimulants. The in vitro IgM-RF response to TT did not require a recent in vivo TT booster immunization and was observed at an antigen does that elicits polyclonal B cell activation but not IgG specific anti-TT antibody. TT-induced IgM RF responder cultures demonstrated higher levels of total IgG and total IgM production than cultures not secreting IgM RF in response to TT. These results indicate that IgM RF production is a concomitant of the polyclonal B cell response elicited by a conventional antigen. Unlike other model systems, this antigen-induced RF response was not mediated by the action of IgG antibody containing immune complexes.