The random recombination and deletion hypothesis for the control of isotype commitment in antibody responses was directly tested in a serial transfer system in vivo. Normal or hyperimmune spleen cells were used in weekly serial transfers with antigen into irradiated recipients until clonal senescence was observed. Antigen-specific and -nonspecific plaque-forming cells of all isotypes were determined at each transfer time. No major changes in the isotypes of specific antibodies were observed for the whole life-span of the transferred cells (9-10 wk), and no indication was obtained for the accumulation of cells transcribing the most 3' members of the C-gene cluster with sustained proliferation. Rather, the dominant isotypes were found throughout the response to be IgG1, IgG2b, and IgG2a. The results imply isotype-specific regulatory mechanisms in the control of Ig class production. These appear to operate as well in the antigen-nonspecific component of the immune response.