THE B-lymphocyte-restricted glycoprotein CD22 is expressed on mature IgM(+) IgD(+) B cells(1-3), and is capable of binding to ligands on T and B cells(2,4-7). CD22 can interact with both the B-cell antigen receptor (BCR) complex(8,9) and signalling molecules, including the protein tyrosine phosphatase SHP1 (PTP1C, SHP)(10-12), a putative negative regulator of BCR signalling(13,14). Thus CD22 may facilitate interactions with lymphocytes and regulate the threshold of BCR signalling(1,11,13). To define the in vivo function of CD22, we generated CD22-deficient mice. Here we show that CD22 is required for normal antibody responses to thymus-independent antigens and regulates the lifespan of mature B cells.