Two different lines of C57BL/6 mice (IgHb) carrying complete rearranged mu chain genes from BALB/c (IgMa) were analyzed for the expression and secretion of endogenous as well as transgenic immunoglobulins at the level of single cells. Quantitation of B cells expressing endogenous IgMb by cytofluorometry, limiting dilution analyses of clonal precursors and secretory cell assays revealed a marked selective expansion, activation and terminal differentiation of those cells producing endogenous immunoglobulins. Thus, the very infrequent IgMb-bearing B cells produced in bone marrow of transgenic mice accumulate in spleen, where they are activated and account for roughly half of all natural immunoglobulin-secreting cells. These observations indicate that mu-transgenic mice are valuable in studies of the antibody repertoire selection operating in unprimed animals but their use could be misleading in the analyzing "monoclonal" immune system.