The influence of the xid gene on murine autoimmunity was investigated by precursor frequency analysis of anti-DNA-producing B cells in non-xid and congenic xid autoimmune and normal mice. Antibody responses were induced in vitro by lipopolysaccharides under limiting-dilution conditions with IgM anti-DNA and antitrinitrophenyl (TNP) determined as models of an autoantibody and nonautoantibody, respectively. All mice demonstrated high frequencies of precursors for anti-DNA without differences between the autoimmune (NZB and MRL-lpr/lpr) and nonautoimmune (CBA/J and DBA/2) strains. In these strains, the presence of the xid gene was associated with a marked reduction of anti-DNA. For NZB.xid mice, this loss of anti-DNA precursors was much greater than that for anti-TNP precursors, whose frequency was similar to that of NZB mice. In contrast, xid-bearing CBA/N, DBA/2.xid, and MRL.xid mice showed marked reductions in both anti-DNA and anti-TNP precursors relative to non-xid mice. The intact anti TNP response of NZB.xid mice may be an additional manifestation of immune abnormalities of the NZB strain and suggests that their B-cell populations differ from those of other mice in the conditions for activation. Since NZB.xid spleens had a preferential reduction of anti-DNA responses, this result suggests that in NZB mice precursors for anti-DNA antibodies are predominantly distributed in the B-cell subset affected by xid, explaining the abrogation of their autoantibody production. The equivalent number of precursors in non-xid mice indicates, however, that additional regulatory abnormalities underlie the change from precursor to autoantibody-producing B cell.