The action of the immunosuppressive agent cyclosporine (CsA) on anti-DNA B-cell responses was investigated in an in vitro system. Spleen cells from autoimmune MRL-lpr/lpr or control BALB/c mice, when cultured at high cell density, spontaneously produced significant amounts of IgM and IgG, including anti-DNA. IgG levels, both total and anti-DNA, were much higher for MRL-lpr/lpr cells compared to BALB/c cells, suggesting similarity of this model system to the in vivo response. For cells of both strains, the production of IgM and IgG anti-DNA was 10- to 100-fold more sensitive to the inhibitory activity of CsA than total immunoglobulin production. The effect was not manifest, however, in cultures stimulated with the B-cell mitogen, lipopolysaccharide. These observations suggest that CsA in certain dose ranges preferentially inhibits anti-DNA production, with efficacy determined by the mechanisms promoting B-cell hyperactivity.