The investigation of the fine specificities of antinuclear antibodies (ANAs) has been fruitful in terms of the nosology and immunopathogenesis of human autoimmune syndromes. Particular reactivities serve as "markers," in that patients with certain syndromes have a much higher incidence of such ANAs than do patients with other diseases. In this category is the almost exclusive against the nuclear acidic protein Sm. Reactivity to Sm can be detected by precipitation in agar, complement fixation, or passive hemagglutination (1,2). Autoimmune mouse strains have also provided a fertile field for the investigation of the basic phenomena of self-activity. In particular, the NZB strain and its hybrid NZB x NZW have been considered excellent models for human SLE and have therefore been studied in great detail (3,4). In addition, Murphy et al at The Jackson Laboratory, Bar Harbor, Maine, have developed several new inbred mouse strains that spontaneously develop SLE-like syndromes (5,6). These are the BXSB strain, which has a male dominant disease characterized by little antiative DNA antibody; the MRL/1, which develops massive, nonmalignant lymphadenopathy, associated with enormous increases in serum immunoglobulin levels and fulminant renal disease; and the MRL/n, which does not develop SLE-like disease until well into the 2nd yr of life, but like the MRL/1 develops high titers of ANA and fatal glomerulonephritis. The MRL/1 differs from MRL/n in only about 10 percent of its genome, including the gene responsible for the MRL/1's lymphoproliferation. In the current study, we have used the technique of double immunodiffusion (ID) in agarose with standard human reference sera (of known ANA specificity) to survey a large number of mice from the NZB x NZW, MRL/1, MRL/n, BXSB, and other strains. We report here the finding of the anti-Sm marker" antibody almost uniquely in MRL/1 and MRL/n animals. These two related strains may serve as experimental models to explore the mechanism stimulating the production of this unique autoantibody in SLE.