Previous studies have suggested that the CDR3 genetic element of the heavy chain variable region of autoantibodies is important in determining reactivity against self antigens, particularly against DNA. The lpr mutation was recently found to encode for a defective form of the fas protein, a molecule important for the transmission of the apoptotic signal into cells. Our aim was to determine whether CDR3 elements similar to those described for autoantibody-producing hybridomas derived from lupus-prone strains could be found in the preimmune repertoire of B cells in mice with the lpr mutation. The analysis of the junctions of the VH-C mu functional rearrangements derived by polymerase chain reaction (PCR) amplification of RNA obtained from splenic small, resting cells stimulated with lipopolysaccharide (LPS) from male lpr mice showed that a large proportion of them expressed D genes in the unusual reading frames 2 and 3. Two of the lpr joints were formed by D-D fusions. Similarly, nearly half of the lpr sequences had arginines, an amino acid which promotes binding to dsDNA and is seldom observed in normal junctions. Our results show that the preimmune repertoire of lpr animals has abnormal CDR3 elements which may result from a failure at different levels of selection. The antigen-dependent selection of such elements that leads to the expansion of specific, high-affinity anti-dsDNA antibody-producing clones might depend on other genetic factors not found in the C57B1/6-lpr strains but in the MRL-lpr.