The mechanism and specificity of isotype switching operative in human B lymphocytes was investigated by a determination of immunophenotype and immunoglobulin heavy and light chain gene status in a panel of human Ig-, IgM, IgG, and IgA B cell malignancies. Regardless of specific tumor type or switched immunophenotype, isotype switching was accompanied by the rearrangement of the expressed C(H) gene downstream of VDJ(H), with concomitant deletion of upstream C(H) genes in all cases. On the allelically excluded chromosome, 25% of the IgG or IgA tumors have retained Cμ, and 75% have deleted Cμ. The 5' recombination breakpoints for both productive and excluded alleles lie within or near Sμ, 3' of the enhancer. No correlation between the extent of allelically excluded C(H) deletions and the isotype produced by the tumor was observed. Excluded chromosome deletion endpoints were found 5', equal to, or 3' of productive chromosome deletion endpoints. Furthermore, we have identified at least one IgM+ tumor that has undergone abortive C(H) gene deletions and have observed several unanticipated switch region deletions and potential translocations. The data suggest that isotype switching in human B cells occurs by a nonsubclass- and nonclass-specific switch recombinase.