B ackground genes determine the incidence and severity of lymphoaccumulation and histopathologic manifestations of systemic autoimmunity in mice homozygous for the apoptosis-defective Faslpr mutation. By interval mapping of 274 F2 mice intercrossed between MRL-Faslpr (severe disease) and C57BL/6-Faslpr (minimal disease), four loci were identified with significant linkage to lymphadenopathy and/ or splenomegaly on chromosomes 4, 5, 7, and 10, which were named lupus in (MRL-Faslpr x B6-Faslpr)F2 cross1-4 (Lmb1-4), respectively. Lmb1, -2, and -3 were also linked to the production of anti-dsDNA antibodies, but not glomerulonephritis, whereas Lmb4 was associated with glomerulonephritis. Lmb2, -3, and -4 were inherited from the MRL background, but interestingly, Lmb1 was derived from the C57BL16-Faslpr. Nevertheless, each locus, regardless of the strain of origin, appeared to act in an additive manner, although certain combinations were more effective. Only a single suggestive locus on chromosome 1 could be correlated with arthritis. The identification of loci with highly significant linkage to disease manifestations in Faslpr strains will make it possible to map and clone new genetic defects contributing to autoimmunity.