Highly inbred MRL-Ipr/Ipr.xid congenic mice were bred and compared with their + littermates. The xid-bearing congenics developed lymphadenopathy consisting of dull Ly-1+ T cells and impairment of cellular proliferation and IL 2 production in response to the T cell mitogen Con A. Thus, the lpr gene was fully expressed. The xid gene, however, was also expressed as indicated by the failure to respond to immunization with TNP-Ficoll and flow cytometric analysis of splenic B cells. The xid gene was associated with a marked reduction in IgM anti-ssDNA and anti-nDNA of both classes, and serum Ig-bound gp 70. Kidney disease was markedly retarded as was death from the autoimmune process. These studies suggest that the T cell lymphoproliferation and dysfunction characteristic of MRL-Ipr/Ipr mice is not sufficient to induce accelerated autoimmunity; xid is able to markedly slow the process. The xid gene interferes with the development of a B cell subset necessary for maximum autoantibody production, anti-gp 70 production, and the resultant immune complex renal and cardiac disease. The present finding of protection against accelerated autoimmunity in MRL-Ipr/Ipr mice by xid, coupled with previous demonstrations of protection against autoimmunity in other autoimmune mouse strains, suggests that a common approach to the therapy of systemic lupus may be possible.