B lymphocytes can be rendered specifically unresponsive to antigen by experimental manipulation in vivo and in vitro^1–6, but it remains unclear whether or not natural tolerance involves B-cell tolerance because B cells are controlled by T lymphocytes, and in their absence respond poorly to antigen (reviewed in ref. 7). In addition, autoantibody-producing cells can be found in normal mice and their formation is enhanced by B-cell mitogens such as lipopolysaccharides^8–12. We have studied B-cell tolerance in transgenic mice using genes for IgM anti-H–2^k MHC class I antibody. In H–2^d transgenic mice about 25–50% of the splenic B cells bear membrane immunoglobulin of this specificity, and abundant serum IgM encoded by the transgenes is produced. In contrast, H–2^k x H–2^d (H–2-d/k) transgenic mice lack B cells bearing the anti-H–2^k idiotype and contain no detectable serum anti-H–2^k antibody, suggesting that very large numbers of autospecific B cells can be controlled by clonal deletion.