A subset of B lymphocytes present primarily in the peritoneal and pleural cavities is defined by the expression of CD5 and is elevated in autoimmune diseases. Upon signaling through membrane immunoglobulin M (mIgM), splenic B lymphocytes (B-2) proliferate, whereas peritoneal B cells (B-1) undergo apoptosis. However, in CD5-deficient mice, B-1 cells responded to mIgM crosslinking by developing a resistance to apoptosis and entering the cell cycle. In wild-type B-1 cells, prevention of association between CD5 and mIgM rescued their growth response to mIgM crosslinking. Thus the B cell receptor-mediated signaling is negatively regulated by CD5 in normal B-1 cells.