The basis of immune memory leading to heightened secondary antibody responses is a longstanding unanswered issue. Here we show that a single irreversible molecular change in the B cell antigen receptor, which is brought about by immunoglobulin M (IgM) to IgG isotype switching, is sufficient to greatly increase the extrafollicular proliferative burst of antigen-specific B cells. The unique membrane-spanning regions of IgG do not alter the T cell–dependent activation and proliferation of antigen-specific B cells in vivo, but markedly increase the number of progeny cells and plasmablasts that accumulate. These results establish a key molecular determinant of immunological memory and define an unexpected cellular basis by which it enhances the magnitude of secondary antibody responses.