Insoluble anti-mouse Fab is a strong mitogen for isolated mouse B lymphocytes, but by itself fails to induce differentiation to antibody secretion. We have recently found that addition of a 24 hour supernatant of ConA activated spleen cells causes enhanced and sustained proliferation and differentiation to antibody secretion in cultures activated by isoluble anti Ig. The supernatant alone has little effect on isolated B lymphocytes. B lymphocytes from CBA/N mice or (CBA/N x Balb/C) males do not respond to isoluble anti Ig. This novel separation of a proliferative signal delivered via surface Ig and a differentiative signal from accessory cells in a polyclonal response creates an experimental system which haq important advantages for direct study of regulation of B lymphocytes by surface Ig and accessory cells.