The molecular mechanisms leading to anti-double-stranded (ds) DNA antibody production in systemic lupus erythematosus (SLE) are poorly understood. We describe here the immunoglobulin variable region genes of six human hybridomas secreting IgG anti-dsDNA antibodies derived from three SLE patients. The monoclonal IgG anti-dsDNA antibodies have been shown to be of high affinity and no multireactivity was observed (Winkler et al., Clin. Exp. Immunol., 1991. 85: 379). The comparison of the variable region genes expressed in the hybridomas with known germ-line genes as well as with the germ-line counterparts from one patient shows that the VH and VL sequences are somatically mutated. The pattern and extent of the observed somatic mutations are suggestive for an antigen-driven selection of at least four of these B cell clones. Several VH and VL genes used by the hybridomas were found to be expressed in the natural antibody repertoire, in the restricted fetal repertoire and in B cell malignancies expressing the CD5 antigen.