Autoimmune MRL-lpr/lpr and NZB/W mice spontaneously secrete large quantities of pathogenic IgG1 and IgG2a autoantibodies. NZB mice also produce autoantibodies but these tend to be of the IgM H chain class. This work examines whether differences in the isotype of autoantibody produced by lupus-prone mice reflects differences in the sensitivity of autoreactive B cells to lymphokine-mediated IgG secretion. Twenty-five percent of normal BALB/c B cells produced IgG1 when stimulated in vitro with IL-4 plus LPS. This was comparable with the effect of IL-4 on small resting B cells from MRL-lpr/lpr and NZB/W mice. In contrast, less than 8% of the resting B cells from NZB mice produced IgG1 under these conditions. LPS plus IFN-gamma induced 5% of BALB/c and NZB/W but only 1% of NZB B cells to secrete IgG2a. Because lymphocytes from both young and old NZB mice showed diminished IgG1 and IgG2a secretion after lymphokine treatment, B cells from this strain appeared to be intrinsically resistant to the effects of IL-4 and IFN-gamma. In contrast, a disproportionately large proportion (22%) of B cells from adult MRL-lpr/lpr mice produced IgG2a when treated with IFN-gamma in vitro. Only B cells from MRL-lpr/lpr mice with active disease responded with such high levels of IgG2a production: cells from animals that had not yet developed clinical disease produced normal levels of IgG2a. Within each strain, B cells producing antibodies against autoantigens such as DNA, bromelain-treated mouse RBC and Sm responded to treatment with IL-4 and IFN-gamma in a manner indistinguishable from B cells producing antibodies against conventional Ag such as TNP and ARS.