To study the significance of developmentally restricted VH gene expression, and natural self-reactive B lymphocytes, VH81X-μ-heavy chain transgenic mice were constructed and the expression of this gene analysed at different stages of development and in different B-cell subsets. It was found that the majority of B cells expressed the transgenic heavy chain associated with different κ but not λ light chains. These B cells were predominantly self reactive and distributed normally to peripheral lymphoid organs. Among the CD23-/IgM(hi) B cells of transgenic mice there was a population of clonally unrelated relatively self-reactive B cells that expressed identical antigen receptors but did not secrete antibody. Continued administration of antibody of the same specificity during post-natal development reduced the generation of these B cells to very low levels. These studies show that although natural self-reactive B cells are continuously generated as a result of positive selection by self-antigen, their maturation may be blocked at the CD23-/IgMhi stage. Their failure to enter the CD23+ IgM(lo) B cell pool may prevent them from receiving T-cell help and production of high affinity potentially pathogenic autoreactive IgG antibodies.