Xenogeneic and allogeneic antisera to the major envelope glycoprotein (gp71) of murine leukemia viruses (NyLV) inhibited the mitogenic response of normal mouse splenic lymphocytes to phytohemagglutinin (PHA) and lipopolysaccharide (LPS). This inhibition was specific for gp71 as demonstrated by the inability of xenogeneic antisera to other viral glycoproteins or structural proteins to inhibit and by the ability of purified antigens to block specifically the inhibitory effect. The ability of antisera to gp71 to inhibit LPS responses, however, is highly dependent on the strain and age of mouse spleen cells used and appears correlated with the expression of endogenous viruses. Moreover, the preferential inhibition of LPS responses suggests that this expression may be predominately B cell specific. The results suggest that the inhibitory effect is mediated via antibody binding to lymphocytes and that expression of viral envelope antigens on the cell surface which bind immunoglobulins can block or interfere with the binding or uptake of mitogens. A variety of natural mouse immune sera and "tumor" sera, having antibodies directed against gp71, can similarly inhibit mitogen responses; and this inhibition can be specifically blocked with MuLV or gp71.