We have identified two important molecules involved in the regulation of B cell differentiation, namely Lyb-2 and Ly-5. To gain further insight into the function of these two molecules, we examined the effect of monoclonal Lyb-2 and Ly-5 antibodies on lipopolysaccharide (LPS)-induced B cell growth and maturation. We found that Lyb-2 antibody does not have any effect on LPS-induced proliferation and on polyclonal IgM or total IgG responses. On the other hand, although Ly-5 antibody did not affect proliferation and polyclonal IgM responses, it strongly inhibited polyclonal IgG responses, presumably by direct action on B cells. This inhibition was not caused by direct suppressive effect of Ly-5 antibody or Fc receptor-mediated negative signaling. To exert maximal inhibitory effect, Ly-5 antibody had to be added to the culture during the initial 48 hr. However, the presence of Ly-5 antibody during the first 2 days did not cause a significant inhibition. It is thus likely that Ly-5 plays a critical role in the regulation of LPS-induced B cell maturation into IgG-secreting cells at a phase starting within 48 hr after LPS stimulation and continuing thereafter.